symposium future of immunology @ berlin...chiara romagnani, ton schumacher, eric vivier the future...

Institute of Anatomy at Wilhelm-Waldeyer-Haus

Charité Campus Mitte | Philippstr. 12 | 10115 Berlin

Abstract Book

November 21 – 23, 2019

Symposium Future of Immunology @ Berlin

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S c i e n t i f i c A d v i s o r y B o a r d

Frédéric Geissmann (Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, NY)

Erika Pearce(Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg)

Ton Schumacher (The Netherlands Cancer Institute, Leiden University Medical Center)

Eric Vivier (Centre d´Immunologie de Marseille-Luminy (CIML), France)

O r g a n i z i n g C o m m i t t e e

Andreas Diefenbach (Institute of Microbiology, Infectious Diseases and Immunology, Charité)

Frank Heppner (Department of Neuropathology, Charité – Universitätsmedizin Berlin)

Klaus Rajewsky (Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin-Buch)

Reinhold E. Schmidt (Deutsches Rheuma-Forschungszentrum (DRFZ))

Symposium Future of Immunology @ Berlin

N o v e m b e r 2 1 – 2 3 , 2 0 1 9 a t C h a r i t é – U n i v e r s i t ä t s m e d i z i n B e r l i n

What is the Symposium all about?

Immunological research at the highest level has a long tradition at Charité – Universitätsmedizin Berlin and represents a major research focus. In the coming years, the core departments of immunology are facing a generation change at the leadership level, which gives reason to think about strategic and structural amendments to consolidate Charité’s role as a leading institution in the field of immunology – both in basic and clinical translational research. With its broad overlap to other research areas, the field of immunology plays a special role requiring interdisciplinary work and inter-organization networ-king. A unique characteristic is the close networking of Charité researchers with their university and non-university partners in Berlin, which enables a synergistic combination of excellent basic research and clinical research. As of today, immunological research at the Charité is embedded into a network of institutions including the German Rheumatism Research Centre (DRFZ), the Max-Delbrück Center of Molecular Medicine (MDC), the Max-Planck-Institute of Infection Biology and the Robert-Koch-Institute. We are seeking to make use of this excellent research potential and infrastructure even more intensively in the future.

Together with the newly formed Scientific Advisory Board (SAB) consisting of Drs. Erika Pearce (Freiburg, Germany), Eric Vivier (Marseille, France), Ton Schu-macher (Amsterdam, Netherlands) and Frederic Geissmann (New York, USA), we have the ambitious goal of creating optimal conditions for immunological research at the Charité to be carried out at the highest international level in the future.

To jump-start this process, we welcome you to the symposium ‘Future of Im-munology @ Berlin’ which shall serve as an interactive platform to exchange ideas, concepts and visions how to evolve immunology in Berlin in the next decades. The symposium will take place from November 21 – 23, 2019 in Berlin at the Institute of Anatomy (Wilhelm-Waldeyer-Haus), Charité Campus Mitte, Philippstr. 12, 10115 Berlin.

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Day 1 T H U R S D A Y November 21, 2019 Day 2 F R I D A Y November 22, 2019

08.45 History of the Institute for Anatomy at Charité by Thomas Jöns (Charité Instiute for Anatomy)

Session 4 09.00 - 11.00 | Chair: Julia Polansky-Biskup / Hans-Dieter Volk

09.00 Hans-Dieter Volk, Berlin Translational immunology – from pathogenesis to new diagnostics and therapies

Julia Polansky-Biskup, Berlin Utilizing epigenetics for the benefit of Advanced Therapies

09.30 Hedda Wardemann, Heidelberg Qualitative assessments of adaptive immune responses at single-cell level

10.00 Alexander Scheffold, Kiel Antigen-specific regulation of tolerance & inflammation in humans

10.30 Simon Fillatreau, Paris Novel insights into the roles of the adaptive immune system in immune regulati-on and immune-mediated inflammatory diseases

11.00 C O F F E E B R E A K

Session 5 11.30 - 13.30 | Chair: Frederic Geissmann / Eric Vivier

11.30 Eric Vivier, Marseille Harnessing innate immunity in cancer therapy

12.00 Martin Kriegel, New Haven Suppression of translocating pathobionts in autoimmunity – an interventional paradigm for the future of immunology

12.30 Manolis Pasparakis, Köln The intimate connection between cell death and inflammation

13.00 Katja Simon, Oxford Autophagy and Proteostasis in Immune Senescence

13.30 L U N C H (Foyer)

14.30 ROUND TABLE – Panel Discussion | Chair: Andreas Diefenbach / Jens Steinbrink Michela Di Virgilio, Frederic Geissmann, Andreas Radbruch, Klaus Rajewsky, Chiara Romagnani, Ton Schumacher, Eric Vivier The Future of Immunology

15.30 C O F F E E B R E A K (Foyer)

11.15 Opening and Welcome by Heyo Kroemer (CEO Charité)

Session 1 11.30 - 13.30 | Chair: Ton Schumacher / Eric Vivier

11.30 Ton Schumacher, Amsterdam T cell recognition of human cancer

12.00 Burkhard Becher, Zurich Mapping the Immune System in chronic inflammatory diseases: one cell at a time

12.30 Bodo Grimbacher, Freiburg What can rare immuno deficiencies teach us in immunology?

13.00 Gerhard Krönke, Erlangen The road from autoimmunity to inflammation

13.30 L U N C H (Foyer)

Session 2 14.30 - 16.30 | Chair: Gerd-Rüdiger Burmester / Antigoni Triantafyllopoulou

14.30 Gerd-Rüdiger Burmester, Berlin Charité and the DRFZ - A unique model of tight interaction between clinical and translational science

Antigoni Triantafyllopoulou, Berlin Innate immunity at the crossroad of autoimmunity and organ damage

15.00 Axel Kallies, Melbourne Effector differentiation of regulatory and cytotoxic T cells

15.30 Gioacchino Natoli, Milan Accessibility and usage of the genomic regulatory information in immune responses

16.00 Tal Arnon Perivascular pathways direct one-way migration of T cells into splenic T zones

16.30 C O F F E E B R E A K (Foyer)

Session 3 17.00 - 19.00 | Chair: Andreas Radbruch / Chiara Romagnani

17.00 Andreas Radbruch, Berlin | Cellular pathology of chronic inflammatory diseases

Chiara Romagnani, Berlin | Innate immune checkpoints of inflammation

17.30 Georg Schett, Erlangen Towards a molecular profiling of inflammatory disease

18.00 Dietmar Zehn, München InTOXication causes T-cell exhaustion in chronic infection

18.30 Claudia Waskow, Jena Generation and Regeneration of Hematopoietic Stem Cells

20.00 open end > Dinner with Students

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Day 3 S A T U R D A Y November 23, 2019

Session 7 09.00 - 11.00 | Chair: Leif-Erik Sander / Norbert Suttorp

09.00 Norbert Suttorp, Berlin and Leif-Erik Sander, Berlin Host-directed approaches to diagnostics, treatment, and prevention of infectious diseases

09.30 Susanne Herold, Gießen Macrophages – key effector cells in organ damage and injury resolution in the infected lung

10.00 Florian Klein, Köln Broadly Neutralizing Antibodies for HIV-1 Immunotherapy

10.30 Melanie Greter, Zurich Life and Fate of Brain Macrophages

11.00 C O F F E E B R E A K

Session 8 11.30 - 13.30 | Chair: Frederic Geissmann / Ton Schumacher

11.30 Frederic Geissmann, New York Genetic and developmental basis for macrophages functions

12.00 Thomas Gebhardt, Melbourne A new melanoma platform to study spontaneous immunity, cancer-immune equilibrium and immune control of metastatic disease

12.30 Michael Dustin, Oxford Supramolecular attack particles: a new cytotoxic biomaterial

13.00 L U N C H and end of symposium

Session 6 16.00 - 18.00 | Chair: Thomas Blankenstein / Gerald Willimsky

16.00 Thomas Blankenstein, Berlin and Gerald Willimsky, Berlin T-Immunology

16.30 Andrea Schietinger, New York Molecular and epigenetic programs defining tumor-specific T cell differentiation

17.00 Mathias Heikenwälder, Heidelberg On the role of immune cells on NASH/liver cancer and its consequences for therapy

17.30 Florian Greten, Frankfurt a.M. The inflammatory tumor microenvironment

19.00 open end > Dinner at Charité Hörsaalruine

Day 2 F R I D A Y November 22, 2019

Session 1

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Ton Schumacher

“T cell recognition of human cancer”

The Netherlands Cancer InstituteLeiden University Medical CenterThe Netherlands

B I O S K E T C H

Ton N. Schumacher is Principal Investigator at The Netherlands Cancer Institute and Professor of Im-munotechnology at Leiden University, where his research focuses on the dissection and manipulation of T cell recognition of human cancer. Schumacher is recipient of, amongst others, the Amsterdam Inventor Award, Queen Wilhelmina Research Award, Meyenburg Award, and W.B. Coley Award. Next to his academic role, Schumacher is founder of 4 biotechs and venture partner at Third Rock Ventures.

A B S T R A C T

Inhibitors of the immune checkpoint PD-1 show impressive clinical activity in a subset of patients across a range of tumor types. However, little is known on the immunological response that human cancers display upon such PD-1 blockade, and which baseline properties in the tumor microenvironment (TME) can be used to predict immune re-activation by therapy. To address this question, we developed a human tumor explant platform that preserves the TME but allows for perturbation by immunothera-peutics. Using this platform, we have analyzed the immunological response of a cohort of 37 tumors from fi ve cancer types (melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, renal cell carcinoma) to ex vivo PD-1 blockade. Data obtained reveal that immune activation by PD-1 blockade is restricted to approximately 35% of tumors and that such immunological responses correlate with clinical anti-PD-1 response. Furthermore, a number of baseline parameters were defi ned that predict the capacity for immune re-activation by PD-1 blockade. The diversity in the immunological response of human cancers to PD-1 blockade described here, and the identifi cation of correlates of immune re-acti-vation helps explain the divergent response that has been observed clinically.

5 S E L E C T E D P U B L I C A T I O N S

1. Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, Krijgsman O, van den Barber M, Broeks A, van Thienen JV, Mallo HA, Adriaansz S, ter Meulen S, Pronk LM, Grijpink-Ongering L, Bruning A, Gittelman R, Warren S, van Tinteren H, Peeper D, Haanen JB, van Akkooi AC, Schumacher TN. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage 3 melanoma. Nat Med. 2018 https://doi.org/10.1038/s41591-018-0198-0.

2. Mezzadra R, Sun C, Jae LT, Gomez-Eerland R, de Vries E, Wu W, Logtenberg MEW, Slagter M, Rozeman EA, Hofl and I, Broeks A, Horlings HM, Wessels LFA, Blank CU, Xiao Y, Heck AJR, Borst J, Brummelkamp TR, Schumacher TNM. Identifi cation of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017 Sep 7;549(7670):106-110. doi: 10.1038/nature23669. Epub 2017 Aug 16. PubMed PMID: 28813410.

3. Strønen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, Donia M, Böschen ML, Lund-Johansen F, Olweus J, Schumacher TN. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016 Jun 10;352(6291):1337-41. doi: 10.1126/science.aaf2288. Epub 2016 May 19. PubMed PMID: 27198675.

4. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015 Apr 3;348(6230):69-74. doi: 10.1126/science.aaa4971. Review. PubMed PMID: 25838375.

5. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilk-mann H, Atmioui DE, Visser M, Stratton MR, Haanen JB, Spits H, van der Burg SH, Schumacher TN. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med. 2015 Jan;21(1):81-5. doi: 10.1038/nm.3773. Epub 2014 Dec 22. PubMed PMID: 25531942.

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Session 1Burkhard Becher

“Mapping the Immune System in chronic inflammatory diseases: one cell at a time”

Institute of Experimental Immunology-Experimental ResearchUniversity of Zurich, Switzerland

B I O S K E T C H

Burkhard Becher is an immunologist specialized in inflammation research and Director of the Institu-te of experimental Immunology at the University of Zurich in Switzerland. He studied Biology at the University of Cologne in Germany and specialized in Molecular Genetics and Biochemistry. In 1995, for his graduate studies he went to study at McGill University in Canada to train in Neuroimmunology with Jack Antel. His work focused on the role of microglia cells as brain-resident myeloid cells capable of instructing self-reactive T cells in the context of autoimmune neuro-inflammation. In 1999 he joined the lab of Randy Noelle at the Dartmouth Medical School to extend his work to in vivo models of chronic inflammatory diseases and transplantation immunology using innovative transgenic mouse tools. He developed tools to specifically manipulate tissue-resident phagocytes in vivo during inflammation. Burkhard’s focus is the function of cytokines and how these molecules permit cell-cell communication between immune cells. In 2003, he was recruited as Assistant Professor to the University Hospital of Zurich. There he continued to define the cytokine networks in inflammation. In 2008, he became full professor and chairman at the Institute of Experimental Immunology at the University of Zurich and heads the Unit for Inflammation Research.

A B S T R A C T

Chronic inflammatory diseases are mediated by dysregulated immune homeostasis. However, there are still great gaps in our knowledge of inflammatory cascades, in particular in patients who suffer from chronic inflammation. Such knowledge may help to identify biomarkers aiding the diagnosis of the mo-nitoring of disease activity and the identification of therapeutic targets to stop chronic inflammation. One reason for the lack of solid biomarkers is the hypothesis-driven nature of investigations, which bias the investigation toward arbitrarily classified cell subsets and biomarkers. The increasing number of parameters which can be measured simultaneously allow for the concomitant characterization of phenotypic and functional properties at the single cell level and led to major discoveries including new cell types, stratifying biomarkers and disease-relevant signatures. The emergence of cytometers capable of measuring more than 100 parameters simultaneously and in large cohort of patients, brings about a new area of biomarker discovery, where intelligent algorithms and computer-aided analysis allow for a thus far unprecedented view onto the single cell proteome. I will discuss recent advances in single cell technologies and how we apply this technology to immunophenotype patients with inflam-matory disease for the identification of disease-relevant signatures for diagnosis, patient stratification and therapy responses.


1. Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, Arvaniti E, Diebold M, Mrdjen D, van der Meer, F, Krieg C, Al Nimer F, Sanderson N, Stadelmann C, Khademi M, Piehl F, Claassen M, Derfuss T, Olsson T and Becher B. GM-CSF and CXCR4 Define a T Helper Cell Signature in Multiple Sclerosis, Nat Med. 2019;25(8):1290-300

2. Komuczki J, Tuzlak S, Friebel E, Hartwig T, Spath S, Rosenstiel P, Waisman A, Opitz L, Oukka M, Schreiner B, Pelczar P and Becher B. Fate-Mapping of GM-CSF Expression Identifies a Discrete Sub-set of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1beta. Immunity. 2019;50(5):1289-304.

3. Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM, Dummer R, Robinson MD, Levesque MP and Becher B. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med. 2018;24(2):144-53.

4. Spath S, Komuczki J, Hermann M, Pelczar P, Mair F, Schreiner B and Becher B. Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System. Immunity. 2017;46(2):245-60.

5. Becher B, Schlitzer A, Chen J, Mair F, Sumatoh HR, Teng KW, Low D, Ruedl C, Riccardi-Castagnoli P, Poidinger M, Greter M, Ginhoux F and Newell EW. High-dimensional analysis of the murine myeloid cell system. Nat Immunol. 2014;15

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Bodo Grimbacher

“What can rare immunodefi ciencies teach us in immunology?”

Scientifi c Director, Center for Chronic Immunodefi ciency, University Medical Center Freiburg

B I O S K E T C H

Academic training • 1988–1995MedicalstudiesinAachen,FreiburgandHamburg

Scientifi c qualifi cations • 2006HabilitationinInternalMedicine,UniversityofFreiburg(Mentor:Prof.H.H.Peter)• 1995DissertationinMedicine,UniversityofFreiburg(Supervisor:Prof.H.Eibel)

Postgraduate Positions • since2011ScientificDirectorandconsultantattheCCI,MedicalCenter-UniversityofFreiburg• 2006-2011ConsultantandHeadofMarie-CurieResearchGroup,Dept.ofImmunology,RoyalFree Hospital & University College London, UK • 2000-2006AssistantlecturerandEmmyNoether-FellowoftheDFG,DivisionofRheumatology and Clinical Immunology, Medical Center – University of Freiburg • 1997-2000Postdoctorate,NIH,NationalHumanGenomeInstitute,Bethesda,MD,USA• 1995–1997Postdoctorate,DivisionofRheumatologyandClinicalImmunology, Medical Center - University of Freiburg

A B S T R A C T

Primary immune defi ciencies are „an experiment of nature“ (Robert Good). The severity of the immune defect in patients is variable, hence, the fi tness of the immune system in humans rather represents a bell-shaped curve with very few individuals suffering from severe immune defi ciencies, and many more suffering from milder forms of immune incompetence. The work of Prof. Grimbacher hypothesizes that the genetic make-up of each individual has a major impact on the fi tness of the immune system. He therefore searches for genetic variants explaining immune dysregulation. His group was successful in the identifi cation of several monogenetic defects in disorders such as congenital neutropenia, chronic mucocutaneous candidiasis, infl ammatory bowel disease, the hyper-IgE syndrome, and several forms of antibody defi ciencies. Prof. Grimbacher will demonstrate how patients with primary immune defi ciencies teach us about the biology of the human immune system. He will give examples including Candida control, infl ammatory bowel disease, and antibody production. He will give examples of how primary immune defi ciencies aided in the identifi cation of specifi c “Achilles heels” in the immune system, which are now being targe-ted in more prevalent diseases such as B cell lymphomas, and in future possibly also in autoimmune- or atopic conditions, or in multiple myeloma.


1. Rauer S, Marks R, Urbach H, Warnatz K, Nath A, Holland S, Weiller C, Grimbacher B. Treatment of Progressive Multifocal Leukoencephalopathy with Pembrolizumab. N Engl J Med. 2019. (letter) Apr 25;380(17):1676-1677.

2. Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC, Bulashevska A, Proietti M, Fröbel P, Nöltner C, Yang L, Rojas-Restrepo J, Langer N, Winzer S, Engelhardt KR, Glocker C, Pfeifer D, Klein A, Schäffer AA, Lagovsky I, Lachover-Roth I, Béziat V, Puel A, Casanova JL, Flecken-stein B, Weidinger S, Kilic SS, Garty BZ, Etzioni A, Grimbacher B. ZNF341 controls STAT3 expression and thereby immunocompetence. Sci Immunol. 2018. 15;3(24).

3. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, Winzer S, Bulashevska A, Scerri T, Leung E, Jordan A, Keller B, de Vries E, Cao H, Yang F, Schäffer AA, Warnatz K, Browett P, Douglass J, Amera-tunga RV, van der Meer JW, Grimbacher B. Haploinsuffi ciency of the NF-κB1 Subunit p50 in Common Variable Immunodefi ciency. Am J Hum Genet. 2015. 97(3):389-403.

4. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schäffer AA, Grüning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Sene-viratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LS*, Sansom DM*, Grimbacher B*. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014. 20(12):1410-6.

5. Glocker, E. O., D. Kotlarz, K. Boztug, E. M. Gertz, A. A. Schaffer, F. Noyan, M. Perro, J. Diestelhorst, A. Allroth, D. Murugan, N. Hatscher, D. Pfeifer, K. W. Sykora, M. Sauer, H. Kreipe, M. Lacher, R. Nustede, C. Woellner, U. Baumann, U. Salzer, S. Koletzko, N. Shah, A. W. Segal, A. Sauerbrey, S. Buderus, S. B. Snapper, B. Grimbacher, and C. Klein. Infl ammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009. 361: 2033-2045.

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Session 1

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Session 1Gerhard Krönke

“The road from autoimmunity to inflammation”

Translational Immunology,Medicine 3,University Clinic Erlangen

B I O S K E T C H

After graduating from the Medical University of Vienna in 2002, Gerhard Krönke worked as postdoctoral researcher at the Medical University of Vienna (2002-2004) and the University of Virginia, Charlottesvil-le (2004-2006). From 2006-2015 he conducted his clinical training in Internal Medicine and subsequently in Rheumatology at the University Hospital Erlangen, where he is currently working as Senior Physician at the Department of Internal Medicine 3 since 2012. In 2016, he was appointed Professor of Translati-onal Immunology at the University of Erlangen-Nürnberg. His research focuses on cellular, molecular and metabolic pathways involved in the maintenance and break of immunological self-tolerance as well as the onset and resolution of inflammation. In particular, he is trying to understand the mechanisms and events leading to the development of inflammatory autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematodes and to develop novel strategies for their diagnosis and treatment. In 2014 he received an ERC Starting grant and is currently acting as the spokesperson of the DFG research unit FOR2886 “PANDORA” (Pathways triggering AutoimmuNity and Defining Onset of early Rheumatoid Arthritis).

A B S T R A C T

Chronic inflammatory and autoimmune diseases are prevalent disorders that represent a major burden for patients and society. The reasons for a failure in immune tolerance and onset of inflammation in such individuals remain incompletely understood. During the last years, we have sought to unravel underlying mechanistic and molecular aspects such as the contribution of myeloid cells to the main-tenance of tissue homeostasis, self-tolerance and autoimmunity-induced inflammation as well as the exact role of T and B cells during the pathogenesis of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). These insights do not only help to understand basic aspects of innate and adaptive immunity during health and disease, but might additionally aid the development of novel di-agnostic and therapeutic approaches in the near future. Examples include the current development of metabolic MRI techniques that aim to decipher the molecular patterns of musculoskeletal inflammation in a non-invasive manner as well as a clinical trial that seeks to re-induce immune tolerance in patients suffering from RA by sequentially targeting B and T cells.


1. Culemann S, Grüneboom A, Nicolás-Ávila JÁ, Weidner D, Lämmle KF, Rothe T, Quintana JA, Kirchner P, Krljanac B, Eberhardt M, Ferrazzi F, Kretzschmar E, Schicht M, Fischer K, Gelse K, Faas M, Pfeifle R, Ackermann JA, Pachowsky M, Renner N, Simon D, Haseloff RF, Ekici AB, Bäu-erle T, Blasig IE, Vera J, Voehringer D, Kleyer A, Paulsen F, Schett G, Hidalgo A and Krönke G. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature. 2019 Aug 7. In press

2. Pfeifle R, Rothe R, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Ma-gorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y Koeleman CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G and Krönke G. Regulation of autoantibody activity by the IL-23/Th17 axis promotes the onset of autoimmune disease. Nat Immunol. 2017 Jan;18(1):104-113

3. Rothe T, Gruber F, Uderhardt S, Ipseiz N, Rössner S, Oskolkova O, Blüml S, Leitinger N, Bi-cker W, Bochkov VN, Yamamoto M, Steinkasserer A, Schett G, Zinser E and Krönke G. 12/15-li-poxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function. J Clin Invest. 2015 May 1;125(5):1944-1954

4. Scholtysek C, Katzenbeisser J, Fu H, Uderhardt S, Ipseiz N, Stoll C, Zaiss MM, Stock M, Böhm C, Kleyer A, Hess A, Engelke K, David JP, Djouad F, Tuckermann JP, Desvergne B, Schett G and Krönke G. PPARβ/δ governs Wnt signaling and bone turnover. Nat Med. 2013 2013 May;19(5):608-13

5. Uderhardt S, Herrmann M, Oskolkova O, Aschermann S, Bicker W, Ipseiz N, Sarter K, Frey B, Rothe T, Voll R, Nimmerjahn F, Bochkov VN, Schett G and Krönke G. 12/15-Lipoxygena-se Orchestrates the Clearance of Apoptotic Cells and Maintains Immunologic Tolerance. Immunity. 2012 May 25;36(5):834-46.

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Session 2Gerd-Rüdiger Burmester

“Charité and the DRFZ - A unique model of tight interaction between clinical and translational science”

Director, Department of Rheumatology and Clinical Immunology Charité - University Medicine Berlin

B I O S K E T C H

Gerd-R. Burmester, MD, is Professor of Medicine and Director in the Department of Rheumatology and Clinical Immunology at the Charité University Hospital, Free University and Humboldt University of Berlin. He earned his medical degree from Hannover Medical School and completed a residency at the Medical School of the University of Erlangen-Nuremberg. He was awarded a postdoctoral fellowship at Rockefeller University in New York, and was a visiting scholar at the Hospital for Joint Diseases, Mount Sinai School of Medicine, New York. He served as President of the German Society of Rheumatology from 2001-2002 and was President of EULAR (European League Against Rheumatism) from 2015 – 2017. Since 2017, he is President of the Board of Trustees, FOREUM Foundation for Research in Rheumatology. His awards include the Jan van Breemen Medal of the Dutch Society of Rheumatology, the Carol-Nach-man Price, and he was chosen as Master of the American College of Rheumatology in 2019.

As partner of the DRFZ, his clinical interests focus on inflammatory joint diseases and systemic autoim-mune disorders, where he was involved in the major new therapeutic approaches including biologics, autologous stem cell transplantation and JAK-inhibitors. Translational research includes the role of immune response genes in rheumatic diseases, the delineation of immune cells in tissue sites of in-flammation and the analysis of biomarkers in rheumatology.

A B S T R A C T

Rheumatic and musculoskeletal diseases (RMDs), including systemic autoimmune diseases, lead to a great burden both for the affected patients and for the society as a whole with premature disability, loss of working hours and - if uncontrolled - a lower life expectancy. They are also one of the three main reasons why a patient visits a family doctor or specialist. The Department of Rheumatology and Clinical Immunology of the Charité and the German Rheumatology Research Center (DRFZ) tightly work together to meet the challenges of optimal disease recognition including modern epidemiology as well as novel diagnostic and therapeutic approaches. There is a close cooperation between epidemiologists, natural scientists and physicians from all areas of rheumatology research. We recognize that, despite major advances, there is still a great need to develop new treatment modalities. Our ultimate goal will be the cure of RMDs, and where this is not possible, a sustained remission without damage and pain. These approaches started and are ongoing in the areas of re-directing or modulating the immune sys-tem with biologic treatment strategies, an “Immune Reset“ with autologous stem cell transplantation, targeting long lived plasma cells using CD38 and the proteasome system as well as IL-2 treatment to generate T regulatory cells in vivo.


1. Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, Zhou Y, Othman AA, Pangan AL, Camp HS. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a ran-domised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 391:2503-2512.

2. Ospelt C, Bang H, Feist E, Camici G, Keller S, Detert J, Krämer A, Gay S, Ghannam K, Burmester GR. Carbamylation of vimentin is inducible by smoking and represents an independent autoantigen in rheumatoid arthritis. Ann Rheum Dis. 2017 76:1176-1183.

3. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, Gruben D, Wallen-stein G, Krishnaswami S, Zwillich SH, Koncz T, Soma K, Bradley J, Mebus C; ORAL Step investigators. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arth-ritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013 381(9865):451-60.

4. Detert J, Bastian H, Listing J, Weiß A, Wassenberg S, Liebhaber A, Rockwitz K, Alten R, Krüger K, Rau R, Simon C, Gremmelsbacher E, Braun T, Marsmann B, Höhne-Zimmer V, Egerer K, Buttgereit F, Burmester GR. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis. 2013 72:844-50.

5. Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, Burmester GR, Arnold R, Radbruch A, Hiepe F. Depletion of autoreactive immunologic memory follo-wed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. 2009 113(1):214-23.

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Session 2Antigoni Triantafyllopoulou

“Innate immunity at the crossroad of autoimmunity and organ damage”

Department of Rheumatology and Clinical Immunology, Charité University Hospital and German Rheumatism Research Centre, a Leibniz Institute, Berlin

B I O S K E T C H

Antigoni Triantafyllopoulou, M.D./Ph.D., is a Rheumatologist in the Department of Rheumatology and Clinical Immunology at the Charité University Hospital and a Liaison Group Leader at the German Rheu-matism Research Centre, Berlin. She earned her medical degree and doctoral title from the National University of Athens Medical School. She then completed a residency in Internal Medicine at the Mon-tefiore Medical Centre, Albert Einstein College of Medicine and a fellowship in Rheumatology at the Hospital for Special Surgery, Weill Medical College of Cornell University, New York, where she showed that macrophages and type I interferons induce severe lupus nephritis (PNAS 2010). In 2009 she joined the Center of Chronic Immunodeficiency and the Department of Rheumatology in Freiburg University Medical Center. Her group found that DNA damage signaling induced by persistent inflammatory stimuli promotes the formation of polyploid granuloma macrophages with tissue remodelling signatures (Cell 2016). For her work in granuloma macrophages she has been awarded a European Union Marie Curie International Reintegration Grant (2011-2014) and recently an ERC Starting Grant (DDRMac, 2018). In 2017, Antigoni moved to Berlin where she built up a group on Innate Immunity in Rheumatic Diseases. Besides basic research, she runs an outpatient clinic for SLE patients

A B S T R A C T

Autoimmunity may be necessary but is often not sufficient for organ damage. The conditions under which organ damage occurs remain largely unknown and are key to successful treatment approaches. To explore these conditions, we have interrogated the significance, function and crosstalk of innate immune cells in an animal model of systemic lupus erythematosus, a prototypic autoimmune disease. Our data support that innate immunity critically amplifies autoantibody mediated tissue damage in a pathway independent of systemic loss of tolerance. These findings deepen the gap between loss of tolerance and tissue damage and reveal nodes in disease pathogenesis that can serve as treatment targets.


1. Gronke, K, P.P.Hernández PP, Zimmermann J, Klose C.S.N., Kofoed-Branzk M, Guendel-Rojas F, Wit-kowski M, Tizian C, Amann L, Schumacher F, Glatt H, Triantafyllopoulou A, and Diefenbach A. 2019. Interleukin-22 protects intestinal epithelial stem cells against genotoxic stress. Nature 566 (7743): 249-253.

2. Viau A, Bienaimé F, Lukas K, Todkar AP, Knoll M, Yakulov TA, Hofherr A, Kretz O, Helmstädter M, Reichardt W, Braeg S, Aschman T, Merkle A, Pfeifer D, Dumit VI,Gubler MC, Nitschke R, Huber TB, Terzi F, Dengjel J, Grahammer F, Köttgen M, Busch H, Boerries M, Walz G, Triantafyllopoulou A, Kuehn EW. 2018. Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney. EMBO J. 37 (15): e98615.

3. Horn V, Triantafyllopoulou A. 2018. DNA damage signaling and polyploid macrophages in chronic

inflammation. Curr Opin Immunol. 50: 55-63.

4. Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Sagar, Erny D, Stefanowski J, Rogell L, Klein C, Gharun K, Follo M, Seidl M, Kremer B, Münke N, Senges J, Fliegauf M, Aschman T, Pfeifer D, Sarrazin S, Sieweke M, Wagner D, Dierks C, Haaf T, Ness T, Zaiss MM, Voll RE, Deshmukh SD, Prinz M, Goldmann T, Hölscher C, Hauser AE, Lopez-Contreras AJ, Grün D, Gorgoulis V, Diefenbach A, Henneke P, and Trian-tafyllopoulou A. 2016. DNA damage signaling instructs polyploid macrophage fate in granulomas. Cell 167: 1264-1280.

5. Triantafyllopoulou A, Franzke C-W, Seshan SV, Perino G, Girardi G, Kalliolias G, Ramanujam M, van Rooijen N, Davidson A, and LB Ivashkiv. 2010. Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci U S A 107:3012-3017.

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Session 2Axel Kallies

“Effector differentiation of regulatory and cytotoxic T cells”

Professor, Molecular Immunology Laboratory, The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne

• HonoraryPrincipalFellow,TheWalterandElizaHallInstituteofMedicalResearch• ResearchFellowoftheNationalHealthandMedicalResearchCouncil(NHMRC)ofAustralia

B I O S K E T C H

Axel Kallies completed his PhD in Berlin, Germany, working on the role of transcription factor IRF8 in the development of macrophages. He then started his postdoctoral fellowship in the group of Stephen Nutt at the Walter and Eliza Hall Institute (WEHI), Melbourne, Australia, where he worked on the control of plasma cell differentiation and established the central role of Blimp1 in this process. In 2010 he started his laboratory at the WEHI and began his research focused on T-cell biology. During this time, his lab focussed on transcriptional regulators in the differentiation of conventional and regulatory T cells. In 2017, he was recruited to the University of Melbourne. His team studies the molecular cont-rol of lymphocyte differentiation in response to antigen with a particular focus on T cells residing in non-lymphoid tissues. His group published several key studies in leading journals of the field, including Science, Immunity and Nature Immunology, which detail the roles of transcription factors and cytokines in differentiation, clonal expansion and cellular metabolism of lymphocytes.The research of the Kallies laboratory focuses on the molecular control of CD8+ cytotoxic and regulato-ry T-cell differentiation with a focus on populations residing in non-lymphoid tissue, including healthy tissues and tumors.

A B S T R A C T

Lymphocyte differentiation is a strictly controlled process that is critical for both immunity and ho-meostasis. My lab studies the molecular control of lymphocyte differentiation in response to antigen, including that of B cells as well as conventional and regulatory T cells. My group has developed and ap-plied genetic and molecular approaches to the field, including novel reporter mouse strains, metabolic and transcriptional profiling, chromatin immunoprecipitation (ChIP) and accessible chromatin (ATAC) sequencing. These studies detailed the roles of key transcription factors and cytokines in differentiati-on, clonal expansion and cellular metabolism of lymphocytes. Over the last years, my lab has developed a focus on the molecular control of lymphocyte populations residing in non-lymphoid tissue, including tumours. This includes studies on the central role of IL-33 in the differentiation of tissue-resident regu-latory T cells, the essential functions of transcriptional regulators Blimp1 and Hobit in the generation of tissue-resident memory T cells and the molecular control of exhausted T cells. In my presentation I will discuss recent discoveries related to the differentiation of regulatory T cells in non-lymphoid T cells and to the maintenance of effector T cells during chronic infection and in tumours.


1. Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, Belz G, Smyth GK, Busslinger M, Nutt SL, Kallies A 2011. The transcription factors Blimp1 and IRF4 jointly control differentiation and function of effector regulatory T cells. Nature Immunology 12, 304-11 (376 cites).

2. Man K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S, Pellegrini M, Belz GT, Smyth GK, Febbraio MA, Nutt SL, Kallies A 2013. The transcription factor IRF4 is essential for TCR affinity-mediated me-tabolic programming and clonal expansion of T cells. Nature Immunology 14, 1155-65 (205 cites).

3. Vasanthakumar A, Moro K, Xin A, Liao Y, Gloury R, Kawamoto S, Fagarasan S, Mielke LA, Afshar-Sterle S, Masters SL, Nakae S, Saito H, Wentworth JM, Li P, Liao W, Leonard WJ, Smyth GK, Shi W, Nutt SL, Koyasu S, Kallies A. 2015 The transcriptional regulators IRF4, BATF and IL-33 orchestrate develop-ment and maintenance of adipose tissue-resident regulatory T cells. Nature Immunology 16, 276-285 (249 cites).

4. Mackay LK, Minnich M, Kragten NAM, Liao Y, Nota B, Seillet C, Zaid A, Man K, Preston S, Freestone D, Braun A, Pellicci DG, Godfrey DI, Belz GT, Pellegrini M, Gebhardt T, Busslinger M, Shi W, Carbone FR, van Lier RAW, Kallies A*, van Gisbergen KPJM* 2016. Hobit and Blimp1 instruct a universal transcrip-tional program of tissue-residency in lymphocytes. Science 352, 459-463. *co-senior authors (232 cites).

5. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, Pellegrini M, Zehn D, Berberich-Siebelt F, Febbraio MA, Shi W, Kallies A 2017. IRF4 promotes T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47, 1129-1141 (44 cites).

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Session 2Gioacchino Natoli

“Accessibility and usage of the genomic regulatory information in immune responses”

Biochemistry, School of Medicine,Humanitas UniversityMilan, Italy

B I O S K E T C H

I am currently Professor of Biochemistry at the School of Medicine of Humanitas University, Milan, whe-re I moved three years ago. Previously I have been working as Principal Investigator at the European Institute of Oncology (IEO) in Milan (06/2005 to 07/2016) and at the Institute for Research in Biomedicine (IRB, Bellinzona, Switzerland) (06/2000 to 06/20005). I was trained as an MD at the University of Rome, where I also obtained my Residency in Internal Medi-cine (1997) before moving to the University of California San Diego (UCSD) for a postdoctoral training in Michael Karin’s lab.

A B S T R A C T

Macrophage gene expression programs and cis-regulatory networks are specified by the interplay bet-ween a hardwired differentiation program that underlies macrophage identity and tissue micro-en-vironmental signals that influence the distinctive properties acquired by these cells in different tissues. Exposure to a variety of danger signals, including molecules released from damaged tissues and mo-lecules associated with -or released by- invading microbes, induces dramatic changes in macrophage gene expression programs and eventually functional properties. The correct and efficient deployment of such programs is essential both to cope with threats to organism survival and to restore homeost-asis. Data obtained in the last years allowed understanding the mechanisms controlling macropha-ge-specific gene expression programs in response to micro-environmental and danger signals. It is now clear that lineage determining transcription factors that specify macrophage differentiation such as PU.1 and IRF8, set the stage for the activity of signal-regulated transcription factors. This entails the constitutive displacement of nucleosomes that occlude genomic regulatory elements required for macrophage-specific gene regulation as well as the cooperation with signal-regulated transcription factors in order to remodel chromatin in response to stimulation and thus enable the stimulus-specific expansion of the accessible repertoire of genomic regulatory elements.


1. Cooptation of tandem DNA repeats for the maintenance of mesenchymal identity (C. Balestrieri, G. Alfarano, M. Milan, V. Tosi, E. Prosperini, P. Nicoli, A. Palamidessi, G. Scita, G.R. Diaferia, G. Natoli). Cell 173:1150-1164 (2018)

2. Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk (Piccolo V., Curina A, Genua M, Ghisletti S, Simonatto M, Sabo‘ M, Amati B, Ostuni R, Natoli G). Nature Immunology 18, 530-540. PMID 28288101 (2017).

3. Latent enhancers activated by stimulation in differentiated cells (Ostuni R, Piccolo V, Barozzi I, Pol-letti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G.) Cell. 152: 157-71 (2013).

4. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages (S. Ghisletti, I. Barozzi, F. Mietton, S. Polletti, F. De Santa, E. Venturini, L. Gregory, L. Lonie, A. Chew, C.L. Wei, J. Ragoussis, G. Natoli) Immunity, 32:317-28. Epub 2010 Mar 4 (2010).

5. The histone H3 lysine 27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing (F. De Santa, M.G. Totaro, E. Prosperini, S. Notarbartolo, G. Testa and G. Natoli). Cell 130, 1083-1094 (2007).

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Session 2Tal Arnon

“Perivascular pathways direct one-way migration of T cells into splenic T zones”

Wellcome Trust Investigator and Senior Kennedy Research Fellow at the Institute of Rheumatology, University of Oxford

B I O S K E T C H

Dr Tal Arnon PhD is a Wellcome Trust Investigator and a Senior Kennedy Research Fellow at the Institute of Rheumatology, Oxford. She obtained a PhD from The Hebrew University (2005) and was trained a postdoctoral Fellow with Professor Jason Cyster in UCSF, before joining the University of Oxford in 2014. Her research focuses on understanding basic mechanisms that regulate lymphocyte trafficking and B cell responses.

A B S T R A C T

Lymphocyte homeostasis and immune surveillance require that naïve T and B cells continuously re-circulate between secondary lymphoid organs. While the mechanisms of lymphocyte entry into lymph nodes has been intensely studied, the manner by which cells traffic within the spleen, the largest of the secondary lymphoid organs, is poorly defined. Here, using intravital microscopy, we reveal unexpected routes and mechanisms used by T cells to enter splenic T zones. We demonstrate that upon initial release in the marginal zone (MZ) and red pulp, T cells join well defined paths that lead them to the bridging channels and connect them directly to T zones. We further show that these paths are formed by vascular structures that act as scaffolds guiding cellular migration in a one-directional manner exclusively towards T zones but not away from them, indicating the existence of distinct entry and exit routes. Examining patterns of cell behaviour during entry further revealed a requirement for a yet unidentified G-protein coupled receptor (GPCR) that is needed for attachment to the entry paths and the existence of a checkpoint located at the gate to the T zone. Taken together, our study uncovers previously unappreciated routes of T cell migration in the spleen, revealing unique structural organiz-ation and mechanisms that evolved to support lymphocyte recirculation via this large systemic organ.


1. Chauveau A, Pirgova G, Cheng HW, De Martin A, Zhou FY, Wideman S, Rittscher J, Ludewig B, and Arnon TI. Perivascular pathways direct one-way migration of T cells into splenic T zones. Under revision (Immunity)

2. Reboldi A, Arnon TI, Rodda LB, Atakilit A, Sheppard D and Cyster JG. B cell interaction with subepithe-lial dendritic cells in Peyer‘s patches is critical for IgA production. (2016) Science 352(6287):aaf4822. JIF: 41.06 .Citation: 71.

3. Arnon TI, Horton BM, Grigorova IL and Cyster JG. Visualization of splenic marginal zone B cell shuttling and follicular B cell egress. (2013) Nature 493(7434):684-8. Citation: 103, JIF: 41.456, PMID: 23263181.

4. Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, Dorn GW, Cyster JG. GRK2-dependent S1PR1 desensitiza-tion is required for lymphocytes to overcome their attraction to blood. (2011) Science 333: 1898-903. Citation: 103, JIF: 41.06, PMID: 21960637.

5. Arnon TI et al. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. (2005). Nature Immunology 6: 515-23. Citation: 259, JIF: 21.80, PMID: 15821739.

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Session 3Andreas Radbruch

“Cellular Pathology of Chronic Inflammatory Diseases”

Professor of Rheumatology and Scientific DirectorDeutsches Rheuma-Forschungszentrum (DRFZ), ein Leibniz Institut Berlin

B I O S K E T C H

Andreas Radbruch is Scientific Director of the DRFZ and Professor of Rheumatology at the Charité Medical School. His recent work addresses the basic organisation of immunological memory, its com-partmentalisation and maintenance, in particular of bone marrow-resident immune memory cells. He has originally described long-lived memory plasma cells and stromal cell niches for immune memory cells. He has developed therapeutic strategies for the ablation of (memory) plasma cells secreting pa-thogenic antibodies. Based on earlier work on the epigenetic and transcriptional imprinting of memory T cells, he has identified molecular adaptations of T cells to chronic inflammation, e.g. the transcription factor Twist1, as novel targets for their selective ablation.Andreas Radbruch did his PhD at the Genetics Institute of Cologne University with Klaus Rajewsky. His early work on antibody class switching has revealed transcriptional targeting of class switch recom-bination by (T cell derived) cytokines, and instruction and selective epigenetic imprinting of cytokine genes in T cells. He has pioneered (cytometric) single cell technologies, in particular the cytometric secretion assay and the MACS technology. He has been President of the German Societies for Rheu-matology and for Immunology, and the International Society for Advancement of Cytometry (ISAC). He is President of the European Federation of Immunological Societies (EFIS). He received the Carol Nachman Prize for Rheumatology and the Avery Landsteiner Award for Immunology.

A B S T R A C T

In refractory patients with chronic inflammatory diseases, therapy-free remission can be achieved by resetting the immune system, i.e. ablating immune cells and regenerating the immune system from stem cells. This identifies experienced and imprinted immune cells as essential and sufficient drivers of inflammation. The “dark side” of immunological memory involves memory plasma cells secreting pathogenic antibodies, and T lymphocytes secreting pathogenic cytokines and chemokines. Single cell-transcriptomes of T cells from the inflamed joints of patients with juvenile idiopathic arthritis reveal cognate activation of these cells in situ. They are refractory to conventional therapies, which aim at the suppression of chronic immune reactions, rather than the maintenance of pathogenic ef-fector cells. Innovative therapeutic strategies can be developed from a molecular understanding of the rules governing their persistence. Here we have identified a key role for mesenchymal stromal cells, preventing metabolic stress-induced apoptosis by induction of PI3K signalling in memory cells. T helper lymphocytes driving chronic inflammation also depend on the transcription factors T-bet and Twist1, to downregulate the pro-apoptotic protein Bim by induction of microRNA 148a, and to force the cells to use fatty acid oxidation, i.e. allow their survival in inflamed tissues. Twist1 is a master regulator of adaptation of pathogenic T helper lymphocytes to chronic inflammation. Genes regulated by it, in particular miR148a, are promising new therapeutic targets.


1. Hradilkova K, Maschmeyer P, Westendorf K, Schliemann H, Husak O, von Stuckrad ASL, Kallinich T, Minden K, Durek P, Grün JR, Chang HD, Radbruch A. Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation. Arthritis Rheumatol. 2019 Oct;71(10):1756-1765.

2. Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grün JR, Löhning M, Radbruch A. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity. 2009 May;30(5):721-30.

3. Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature. 1997 Jul 10;388(6638):133-4.

4. Jung S, Rajewsky K, Radbruch A. Shutdown of class switch recombination by deletion of a switch region control element. Science. 1993 Feb 12;259(5097):984-7.

5. Miltenyi S, Müller W, Weichel W, Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231-8.

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Session 3Chiara Romagnani

“Innate checkpoints of inflammation”

Charité - Universitätsmedizin Berlin (CBF)Med. Klinik m.S. Gastroenterologie, Infektiologie und Rheumatologie and Deutsches Rheuma-Forschungszentrum (DRFZ), ein Leibniz Institut Berlin

B I O S K E T C H

Chiara Romagnani is currently DFG-Heisenberg Professor at the Charité Universitätsmedizin and group leader at the DRFZ. Her team focuses primarily on innate immunity and on investigating how innate lymphoid cells (ILC), especially Natural Killer (NK) cells, respond during inflammatory responses. Her recent work has identified the role of innate receptors in driving activation of ILCs and modulating T cell effector functions, thereby serving as immune checkpoints to modulate chronic inflammation.She received her MD degree from the University of Florence, Italy. After training as oncologist, she obtained in 2006 a PhD in Immunology from the University of Genova under the supervision of Lorenzo Moretta. With an EMBO fellowship, she moved to Berlin and trained as a postdoc at the Deutsches Rheu-ma Forschungszentrum (DRFZ), Berlin, Germany.

A B S T R A C T

Chronic inflammatory disorders can be triggered and maintained by effector mediators produced by experienced immune cells, such as T cell and B cells. In T cells, inflammatory programs are induced by the T cell receptor (TCR) in conjunction with distinct cytokines and/or environmental signals. Innate lymphoid cells (ILCs), including NK cells, exhibit a similar heterogeneity of effector modules, which are activated in the course of inflammation in a TCR-independent manner. The signals and innate receptors instructing the imprinting of different effector programs and their execution in ILCs remain largely unknown. We have studied the innate modules and triggers employed by ILCs, and shared by T cells, which can contribute to promote inflammatory responses in a TCR-independent fashion.


1. Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol. 2018 May;19(5):453-463. doi: 10.1038/s41590-018-0082-6. Epub 2018 Apr 9.

2. Luetke-Eversloh M, Hammer Q, Durek P, Nordström K, Gasparoni G, Pink M, Hamann A, Walter J, Chang HD, Dong J and Romagnani C. Human Cytomegalovirus Drives Epigenetic Imprinting of the IFNG Locus in NKG2Chi Natural Killer Cells. PLoS Pathog. 2014 Oct 16;10(10):e1004441.

3. Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Kno-salla I, Romagnani C. CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood. 2010; Aug 26;116(8):1299-307.

4. Montaldo E, Teixeira-Alves LG, Glatzer T, Hamann W, Babic M, Paclik D, Stölzel K, Gröne J, Lozza L, Juelke K, Matzmohr N, Loiacono F, Petronelli P, Huntington ND, Moretta L, Mingari MC and Roma-gnani C. Human RORγt+ CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity. 2014 Dec 18;41(6):988-1000.

5. Glatzer T, Killig M, Meisig J, Ommert I, Luetke-Eversloh M, Babic M, Paclik D, Blüthgen N, Seidl R, Seifarth C, Gröne J, Lenarz M, Stölzel K, Fugmann D, Porgador A, Hauser A, Karlas A, Romagnani C. RORγt+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activa-ting receptor NKp44. Immunity. 2013 Jun 27;38(6):1223-35.

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Session 3Georg Schett

“Towards a molecular profiling of inflammatory disease”

Professor of Internal Medicine Head of Department Department of Medicine 3 – Rheumatology and Immunology Friedrich-Alexander University Erlangen-Nürnberg, Germany

B I O S K E T C H

Georg Schett is professor of Internal Medicine and since 2006 head of the Department of Medicine 3 - Rheumatology and Immunology – of the Friedrich-Alexander University Erlangen-Nürnberg in Germany. Prof. Schett graduated from the University of Innsbruck (Austria) in 1994. After his dissertation from medical school, he worked as scientist at the Institute of BioMedical Aging Research of the Austrian Academy of Science in Innsbruck. In 1996, he joined the Department of Medicine at the University of Vienna, where he completed his postgraduate training in Internal Medicine and subsequently in Rheu-matology. In 2003 he was promoted to professor of Internal Medicine. Before taking up his position as chair of the Department of Medicine 3, he worked as a scientist in the United States for one year. His scientific work focuses on creating a better understanding of the molecular basis of immune-in-flammatory diseases with rapid translation into clinical practice. Initially, he investigated the immuno-logy of atherosclerosis and focused on antibody-mediated endothelial cell damage. His research work lead to the understanding of the phenomenon of LE-cells in 2007. He was awarded the renowned START Award in 2002 and founded a research group for arthritis in Vienna. Prof. Schett is an ERC award winner and speaker of several DFG- and BMBF-funded joint projects. His work has been awarded numerous prizes, including the Carol Nachman Prize, and published in over 650 scientific articles.

5 S E L E C T E D P U B L I C A T I O N S 1. Culemann S, Grüneboom A, Nicolás-Ávila JÁ, Weidner D, Lämmle KF, Rothe T, Quintana JA, Kirchner

P, Krljanac B, Eberhardt M, Ferrazzi F, Kretzschmar E, Schicht M, Fischer K, Gelse K, Faas M, Pfeifle R, Ackermann JA, Pachowsky M, Renner N, Simon D, Haseloff RF, Ekici AB, Bäuerle T, Blasig IE, Vera J, Voehringer D, Kleyer A, Paulsen F, Schett G, Hidalgo A, Krönke G. (2019) Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature. 572(7771):670-675. Epub 2019 Aug 7.

2. Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici A, Weber S, Matei AE, Chen CW, Maier C, Ka-rouzakis E, Kiener HP, Pachera E, Dees C, Beyer C, Daniel C, Gelse K, Kremer AE, Naschberger E, Stürzl M, Butter F, Sticherling M, Finotto S, Kreuter A, Kaplan MH, Jüngel A, Gay S, Nutt SL, Boykin DW, Poon GMK, Distler O, Schett G, Distler JHW, Ramming A. (2019) PU.1 controls fibroblast polarization and tissue fibrosis. Nature. 566(7744):344-349. Epub 2019 Jan 30.

3. Palumbo-Zerr K, Zerr P, Distler A, Fliehr J, Mancuso R, Huang J, Mielenz D, Tomcik M, Fürnrohr BG, Scholtysek C, Dees C, Beyer C, Krönke G, Metzger D, Distler O, Schett G, Distler JH. (2015) Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis. Nat Med. 21(2):150-8. Epub 2015 Jan 12.

4. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, Lell M, Manger B, Rech J, Naschberger E, Holmdahl R, Krenn V, Harrer T, Jeremic I, Bilyy R, Schett G, Hoffmann M, Herrmann M. (2014) Agg-regated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 20(5):511-7. Epub 2014 Apr 28.

5. McInnes IB, Schett G. (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med. 365(23):2205-19. Review. No abstract available.

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Session 3Dietmar Zehn

“InTOXication causes T-cell exhaustion in chronic infection”

Full Professor – Chair, Division of Animal Physiology and ImmunologySchool of Life Sciences WeihenstephanTechnical University of München

B I O S K E T C H

since 10/2015 Full Professor – Chair, Technical University Munich Area of expertise: Molecular and cellular mechanisms underlying T-cell exhaustion in chronic infections and tumors, Effector and memory T-cell differentiation, Immune tolerance, Autoimmune diseases

2010-2015 Assistant Professor, Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

2009-2010 Research Group Leader Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

2004-2009 Senior Research Fellow, laboratory of Prof. Michael J. Bevan, Howard Hughes Medical Institute / Department of Immunology, University of Washington, Seattle, USA

2004 Graduate (doctorate) student, Prof. Peter Walden, Department of Dermatology, Charité, Berlin, Germany

1996-2004 Charité – Medical School of the Humboldt University Berlin, Germany

A B S T R A C T

Persisting viral infection and cancer can induce a T-cell phenotype known as “exhaustion”. It is cha-racterized by low cytokine production and up-regulated expression of inhibitory receptors and results in a less potent effector response compared to T-cells found in acute infections. From a therapeutic perspective, it is critically important to understand and overcome the transcriptional networks that induce and maintain the “exhausted” phenotype. Several molecules were shown to impact T-cells in chronic infection but none of which act exclusively in chronic infection. We have recently identified that the thymocyte selection-associated high mobility group-box protein (Tox) serves an exclusive role in inducing the exhausted phenotype. While its absence did not impair activation, expansion, and memo-ry-formation of T-cells in acute infection, Tox deficient T-cells retained an acute phenotype in chronic infections. This involved decreased levels of inhibitory receptor expression, more effective virus cont-rol, and a significantly augmented level of immunopathology. Moreover, Tox is critical for maintaining the Tcf-1 positive progenitor T-cell pool. Tcf-1+ T-cells declined rapidly without Tox and, as a consequen-ce, the entire population was rapidly depleted. Overall, we have established that Tox is a key transcrip-tion factor that reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection.


1. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R, Young-blood B, Zehn D. Nature. 2019 Jul;571(7764):265-269. doi: 10.1038/s41586-019-1326-9. Epub 2019 Jun 17.

2. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. Utzschneider DT, Alfei F, Roelli P, Barras D, Chennupati V, Darbre S,

Delorenzi M, Pinschewer DD, Zehn D. J Exp Med. 2016 Aug 22;213(9):1819-34. doi: 10.1084/jem.20150598. Epub 2016 Jul 25.

3. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, Pradervand S, Thimme R, Zehn D*, Held W.* Immunity. 2016 Aug 16;45(2):415-27. doi: 10.1016/j.immuni.2016.07.021. Equal contribution at senior level

4. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Utzschneider DT, Legat A, Fuertes Marraco SA, Carrié L, Luescher I, Speiser DE, Zehn D. Nat Immu-nol. 2013 Jun;14(6):603-10. doi: 10.1038/ni.2606. Epub 2013 May 5.

5. Complete but curtailed T-cell response to very low-affinity antigen. Zehn D, Lee SY, Bevan MJ. Nature. 2009 Mar 12;458(7235):211-4. doi: 10.1038/nature07657. Epub 2009 Jan 28.

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Session 3Claudia Waskow

“Generation and Regeneration of Hematopoietic Stem Cells”

Institute of Aging, Friedrich-Schiller University, Jena, Germany www.WaskowLab.com

B I O S K E T C H

The Waskow laboratory concentrates on fundamental aspects of hematopoietic stem cell biology in-cluding the regulation of fate decisions determining stem cell pool size, heterogeneity, differentiation, and oncogenic transformation. Our research, although basic science in nature, will provide results that can be extended to the modulation of human hematopoiesis for the treatment of hematological disease and trauma.Dr. Waskow performed her thesis studies at the prestigious Basel Institute for Immunology and received her PhD from Basel University. During her postdoctoral phase at Ulm University she published on the role of growth factor receptors in hematopoiesis and on the generation of ‚universal recipient mice‘ that accept allogeneic hematopoietic stem cells. After moving to the Rockefeller University in New York, USA, Dr. Waskow could answer long-standing questions on immune cell turn over and hematopoietic progenitor cell transit though the blood. In 2008, Dr. Waskow started her own group at the Technical University Dresden, where she focused on the regulation of hematopoietic stem cell function of mice and humans to modulate their maintenance, engraftment, and transformation in vivo. This work re-sulted in a number of publications in highly visible journals, and in 2014 Dr. Waskow was promoted to Professor for Immunology in Dresden. Her laboratory recently moved to the Leibniz Institute on Aging in Jena, where she concentrates her scientific program on the regulation of hematopoietic stem cell function, hematopoiesis and immune biology in the aging organism.

A B S T R A C T

The aim of our studies is the identification of cell-autonomous and -extrinsic factors governing main-tenance of hematopoietic stem cells, differentiation, and function of immune cells from mice and hu-mans. This includes the understanding of immune cell homeostasis during steady state and under inflammatory conditions from the embryo to the aged organism. We focus on molecular and cellular mechanisms determining fate decisions of hematopoietic stem and progenitor cells using innovative mouse models suitable for the engraftment of human and mouse hematopoietic stem and progenitor cells established in our laboratory, high-resolution gene expression analysis, combined with quantita-tive single cell transplantations, functional genomics, and mathematic modeling to understand mecha-nisms of HSPC pool size control. I will present an overview about our current research on regulatory pathways important for hematopoietic stem cell maintenance and hematopoiesis in vivo and on the cross-communication between immune cells of distinct developmental origins. The research of my la-boratory, thus, focuses on uncovering fundamental mechanisms that regulate hematopoietic stem cell and immune cell biology to create the basis for new groundbreaking discoveries in mechanistic biome-dicine as a way to improve health throughout life.


1. Jacome-Galarza CE*, Percin GI*, Mueller JT*, Mass E*, Lazarov T, Eitler J, Rauner M, Yadav V, Crozet L, Bohm M, Karsenty G, Waskow C$ and Geissmann F$. 2019 Developmental origin and functional maintenance of osteoclasts. Nature, 568:541-545. IF41.6, *same contribution first author, $co-su-pervised the study

2. Percin GI*, Eitler J*, Kranz A, Fu J, Pollard JW, Naumann R, and Waskow C. 2018 CSF1R regulates the dendritic cell pool size in adult mice via embryo-derived tissue-resident macrophages. Nature Comms, 11;9(1):5279. IF12.4, *same contribution first author

3. Arndt K, Kranz A, Fohgrub J, Jolly A, Bledau AS, Di Virgilio M, Lesche M, Dahl A, Höfer T, Stewart AF, and Waskow C. 2018. SETD1A protects HSCs from activation-induced functional decline in vivo. Blood 131(12):1311-1324. IF13.17

4. Cosgun* KN, Rahmig* S, Mende N, Reinke S, Hauber I, Schäfer C, Petzold A, Weisbach H, Heidkamp G, Purbojo A, Cesnjevar R, Platz A, Bornhäuser M, Schmitz M, Dudziak D, Hauber J, Kirberg J, Waskow C, 2014. Kit Regulates HSC Engraftment across the Human-Mouse Species Barrier. Cell Stem Cell, 15:227-238. * same contribution first author, IF25.91

5. Grinenko T, Arndt K, Portz M, Mende N, Günther M, Cosgun KN, Alexopoulou D, Lakshmanaperumal N, Henry I, Dahl A, Waskow C, 2014. Clonal expansion capacity defines two consecutive developmental stages of long-term hematopoietic stem cells. J Exp Med. 211:209-215. IF13.91

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Session 4Hans-Dieter Volk

“Translational immunology – from pathogenesis to new diagnostics and therapies”

Charité - Universitätsmedizin Berlin: Institute for Medical Immunology and Berlin Institute of Health (BIH): BIH Center for Regenerative Therapies (BCRT) and Labor Berlin Charité Vivantes: Dept. of Immunology

B I O S K E T C H

HDV is W3 professor for “Immunolgy and Regeneration” at the Charité. He is head of the Institute of Medical Immunology, and the BIH- Center for Regenerative Therapies (BCRT), and the Dept.Immunology of Labor Berlin Charité Vivantes GmbH. He is strongly committed for Translational Immunology with research focus on Regeneration and Immu-nology, Transplantation, Infections, and Cell Therapy. He is coordinating the EU-supported international research consortia, PACE (phase 3 cell therapy study: pace-h2020.eu) and RESTORE-Health by Advanced Therapies (restore-horizon.eu), and is member of the steering committees of ReSHAPE undesired im-mune reactions by next generation Treg (reshape-h2020.eu) and HIPGEN (phase 3 cell therapy study: hipeen.eu). Several research projects could be translated to diagnostics on the market. Several biotech companies were founded as spin-offs from the Inst.Med.Immunlogy and BCRT.HDV studied Medicine from 1974-80 and received his MD at 1982 from the Humboldt-University in Berlin focussing on transplantat immunology. After completing his medical specialist training in Immunology, he became head of the clinical immunology department at the Inst.Med.Immunology of the Charite in 1987. From 1987-92 he worked part-time as fellow in the Inst Immunology at the FU Berlin (head: Tibor Diamantstein). Since 1993 he is leading the Inst.Med.Immunology and since 2006 the translational cen-ter BCRT.

A B S T R A C T

The lecture should give a short overview of the immunological research at Institute of Medical Immu-nology and BCRT. Our mission is translational immunology from basic research to new diagnostics and therapies.To achieve this, we have created interdisciplinary structures with partner clinics and institutes. Initially, the focus was on transplantation and infection immunology, more recently also on immunodeficien-cies, autoimmunity, chronic fatigue syndrome, and regenerative medicine. In the field of regenerative therapies (including cell therapies), new structures such as BCRT and BeCAT have emerged, where im-munology and regeneration including cell therapies play a central role. Thus, completely new concepts up to innovative diagnostic/therapeutic approaches could be developed during the last decades, e.g:

- Immunoparalysis in critically ill patients- Risk assessment and targeted immunotherapy of viral infections in immunocompromised patients- Reshaping undesired immune reactions by regulatory T cells - Chronic Fatigue Syndrome and Autoimmunity- Primary immunodeficiencies in adults

- Epigenetic regulation and editing of T-cell functions- Impact of immune balance on challenged tissue homeostasis- Immunogenicity – challenge for gene therapy including gene editing

This translational concept will be explained in more detail using 1-2 examples.


1. Wagner DL, Amini L, Wendering DJ, Burkhardt LM, Akyüz L, Reinke P, Volk HD*, Schmueck-Henneresse M*. High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human popu-lation. Nat Med. 2019 Feb;25(2):242-248. doi: 10.1038/s41591-018-0204-6. Epub 2018 Oct 29.

2. Volk HD, Stevens MM, Mooney DJ, Grainger DW, Duda GN. Key elements for nourishing the transla-tional research environment. Sci Transl Med. 2015 Apr 8;7(282):282cm2. doi: 10.1126/scitranslmed.aaa2049.

3. Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, Dahne M, Hartwig T, Akyüz L, Meisel C, Unterwalder N, Singh NB, Reinke P, Haas NP, Volk HD*, Duda GN*. Terminally diffe-rentiated CD8+ T cells negatively affect bone regeneration in humans. Sci Transl Med. 2013 Mar 20; 5(177):177ra36. doi: 10.1126/scitranslmed.3004754.

4. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-con-trolled multicenter trial. Am J Respir Crit Care Med. 2009 Oct 1;180(7):640-8. doi: 10.1164/rc-cm.200903-0363OC. Epub 2009 Jul 9.

5. Kern F, Surel IP, Brock C, Freistedt B, Radtke H, Scheffold A, Blasczyk R, Reinke P, Schneider-Mer-gener J, Radbruch A, Walden P, Volk HD. T-cell epitope mapping by flow cytometry.Nat Med. 1998 Aug;4(8):975-8

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Session 4Julia Polánsky-Biskup

“Utilizing epigenetics for the benefit of Advanced Therapies”

Charité - Universitätsmedizin Berlin, BCRT-Berlin Institute of Health Center for Regenerative Therapies and Deutsches Rheuma-Forschungszentrum – DRFZ, ein Institut der Leibniz-Gemeinschaft

B I O S K E T C H

JPB is heading a research group at the ‚Berlin Institute of Health Center for Regenerative Therapies (BCRT)‘ at the Charité Universitätsmedizin Berlin, and at the Leibniz institute ‚German Rheumatism Re-search Centre (DRFZ)‘. She was recruited as a professor to the Charité in 06/2019 and became a member of the steering committee of the BCRT. Her group focuses on the clarification of epigenetic mechanisms which contribute to the differentiation, aging and function of immune cells with a special focus on DNA methylation and T lymphocytes. For this, the group generates, analyzes and interprets genome-wide as well as gene-specific epigenetic profiles of primary human T cell populations during health and under diseased conditions. These data sets allow the definition of cell type-specific epigenetic switch regions which might serve a diagnostic biomarkers but at the same time represent promission target structures for precise epigenetic editing methods for the directed manipulation of cellular phenotypes for therapeutic approaches. JPB received her PhD from the Humboldt-University in Berlin already focussing on the epigenetic re-gulation of regulatory T cells. She has worked in several academic research institutions, including the Helmholtz Centre for Infection Research in Braunschweig and the Dana-Farber Cancer Institute at Harvard Medical School in Boston, USA.

A B S T R A C T

Adoptive T cell therapy is a promising approach in various clinical settings, from fighting cancer and chronic infections to combating auto-immunity and graft rejection. For such clinical applications, the expanded T cell products need to be fit and to maintain functional stability during the production pro-cess and after transfusion into the patients. We address these required T cell features from an epigenetic viewpoint and generated genome-wide epigenetic maps for several CD4+ T cell subpopulations. These data allowed the extraction of epigenetic elements essential for the imprinting of functional T cell phenotypes (‚Epi-stabilizers‘) which might be utilized as molecular switches for the targeted induction of advantageous T cell qualities at will. To this end, we established a powerful ‚hit-and-run‘ CRISPR/Cas9-based epigenetic editing approach for the targeted demethylation of Epi-stabilizers. As a proof-of-concept, we were able to induce the immu-no-suppressive master transcription factor FOXP3 from its endogeneous locus by directed epigenetic editing in previously pro-inflammatory human T cells. The induced demethylated state was stable over weeks even after expression of the editing complex has ceased. With this we show, that epigenetic editing is suited to change the molecular profile of T cells and suggest the presented technique as a tool for improving T cell products for advanced cellular therapies.


1. Szilagyi BA, Triebus J, […] Polansky JK*, Hamann A* (2017). Expression of the gut homing receptor integrin α4β7 is stably imprinted in CD4+ memory T cells by epigenetic modification of regulatory regions in the itga4 locus. *shared last authorship. Mucosal Immunology, doi: 10.1038/mi.2017.7.

2. Durek P, Nordström K, Gasparoni G, Kressler C, de Almeida M, Salhab A, […] Polansky JK. (2016) Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development. Immunity, 45, 1148-1161.

3. Polansky JK, et al (2010). Methylation matters: Binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med. Oct;88(10):1029-40.

4. Huehn J, Polansky JK, Hamann A. (2009). Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol. Feb;9(2):83-9.

5. Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008). DNA methylation controls Foxp3 gene expression. Eur J Immunol. 38(6):1654-63.

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Session 4Hedda Wardemann

“Qualitative assessments of adaptive immune responses at single-cell level”

Department of B-cell ImmunologyGerman Cancer Research Center (DKFZ)Heidelberg, Germany

B I O S K E T C H

2014 – present Head of Division Division of B Cell Immunology German Cancer Research Center, Heidelberg, Germany

2006 – 2014 Max Planck Research Group Leader Research Group Molecular Immunology Max Planck Institute for Infection Biology, Berlin, Germany

2003 – 2005 Research Assistant Professor Laboratory of Molecular Immunology, Head: Michel Nussenzweig The Rockefeller University, New York, USA

2001 – 2003 Postdoctoral Associate Laboratory of Molecular Immunology, Head: Michel Nussenzweig The Rockefeller University, New York, USA

A B S T R A C T

Single cell Ig gene amplification and sequencing is increasingly used for the molecular assessment of adaptive antigen receptor repertoires. We have developed a platform for the high-throughput analysis of human and mouse Ig gene repertoires that preserves natural IgH and IgL gene associations and provides full-length Ig gene sequence information for direct gene cloning and the production of recom-binant monoclonal antibodies. Recently, we have established a similar platform for the amplification and cloning of paired human and murine T cell receptor (TCR) alpha and beta chain genes to enable functional assessments of TCRs at single cell level. I will discuss how we use this platform to study the clonal evolution and functional quality of adaptive immune responses in humans, to identify anti-gen-receptors with therapeutic potential, and to develop structure-guided vaccine design strategies.


1. Imkeller K, Scally SW, Bosch A, Martí GP, Costa G, Triller G, Murugan R, Renna V, Jumaa H, Kremsner PG, Sim BKL, Hoffman SL, Mordmüller B, Levashina E, Julien JP, Wardemann H. Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope. Science 360:1358-1362 (2018).

2. Rollenske T, Szijarto V, Lukasiewicz J, Guachalla LM, Stojkovic K, Hartl K, Stulik L, Kocher S, La-sitschka F, Al-Saeedi M, Schröder-Braunstein J, von Frankenberg M, Gaebelein G, Hoffmann P, Klein S, Heeg K, Nagy E, Nagy G, Wardemann H. Cross-specificity of protective human antibodies against Klebsiella pneumoniae LPS O-antigen. Nat Immunol. 19:617-624 (2018).

3. Murugan R, Buchauer L, Triller G, Kreschel C, Costa G, Pidelaserra Martí G, Imkeller K, Busse CE, Cha-kravarty S, Sim BKL, Hoffman SL, Levashina EA, Kremsner PG, Mordmüller B, Höfer T, Wardemann H. Clonal selection drives protective memory B cell responses in controlled human malaria infection. Sci Immunol. pii: eaap8029 (2018).

4. Triller G, Scally SW, Costa G, Pissarev M, Kreschel C, Bosch A, Marois E, Sack BK, Murugan R, Salman AM, Janse CJ, Khan SM, Kappe SHI, Adegnika AA, Mordmüller B, Levashina EA, Julien JP, Wardemann H. Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies. Immunity 47:1197-1209 (2017).

5. Zimmermann N, Thormann V, Hu B, Köhler AB, Imai-Matsushima A, Locht C, Arnett E, Schlesinger LS, Zoller T, Schürmann M, Kaufmann SH, Wardemann H. Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis. EMBO Mol. Med. 8:1325-1339 (2016).

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Session 4Alexander Scheffold

“Antigen-specific regulation of tolerance & inflammation in humans”

Christian-Albrechts-Universität zu Kiel & Universitätsklinikum Schleswig-Holstein, Institut für Immunologie | Arnold-Heller-Str. 3 | Haus U30 | 24105 Kiel | Tel.: 0431 500-31000, Fax: -31004 | [email protected]

B I O S K E T C H

We are studying T cell mediated regulation of tolerance versus immunity and immune pathology in human diseases. We developed sensitive tools for molecular and functional characterization of human T cells reacting against specific antigens relevant for diseases, such as allergy, autoimmunity or inflam-matory bowel disease. Our work contributed to the basic understanding of the antigen-specificity of human Treg cells and their role in allergy and the modulation of human T cell responses by intestinal microbota. Basic understanding of human antigen-specific immunity is a prerequisite for the develop-ment of novel and more specific diagnostic and therapeutic approaches for human immune pathology.After university studies in Chemistry in Freiburg and Cologne, I obtained a PhD in immunology at the University of Cologne in 1997, supervised by Andreas Radbruch. From 1997 to 2007, I established my own lab at the DRFZ Berlin focussing on the T cell mediated regulation of inflammatory disease. From 2007-2011, I was heading a research group at Miltenyi Biotech developing new tools and GMP processes for T cell therapy. From 2012-2018 I was professor for cellular immunology at the Charité-Universitätsmedizin Berlin. Since April 2018 I am the director of the Institute of Immunology at the CAU & UKSH in Kiel.

A B S T R A C T

T helper cells orchestrate adaptive immunity while dysregulated T helper cell responses underlie im-mune pathologies and contribute to their chronification and treatment resistance. Despite their cen-tral role, the identity of the antigen-specific T cells contributing to “health” versus “pathology” is still elusive in many diseases, including allergies, autoimmunity or chronic inflammatory diseases. This is due to technical constraints and often undefined disease-relevant target antigens. In my talk I will dis-cuss our analyses of human antigen-specific T cell responses against airborne antigens and members of the intestinal microbiota as well as autoantigens. We identified antigen-specific regulatory T cells as important mediators of pulmonary tolerance and antigen escape mechanisms enabling Th2 and allergy development. Furthermore, I will discuss the impact of individual members of the microbiota on systemic T cell responses and show that T cell cross-reactivity to an intestinal commensal is a major induction mechanism for Th17 cells contributing to pulmonary inflammation in humans. Finally, the characterization of autoantigen-specific T cells identifies unique alterations in patients with autoim-mune disease. Current technological progress provides unprecedented insight into the details of human immunity and the fundamentals of human immune-mediated diseases, not necessarily predicted by animal models. Understanding these basic processes will help to clarify disease etiopathogenesis and allow develop-ment of targeted therapies.


1. Bacher P, Hohnstein T, Beerbaum E, Röcker M, Blango MG, Kaufmann S, Röhmel J, Eschenhagen P, Seidel K, Rickerts V, Lozza L, Stervbo U, Nienen M, Babel N, Milleck J, Assenmacher M, Cornely OA, Ziegler M, Wisplinghoff H, Heine G, Worm M, Siegmund B, Maul J, Creutz P, Tabeling C, Ruwwe-Glösen-kamp C, Sander LE, Knosalla C, Brunke S, Hube B, Kniemeyer O, Brakhage AA, Schwarz C, Scheffold A. (2019) Instruction of human anti-fungal Th17 immunity and immune pathology by cross-reactivity against a single member of the microbiota. Cell 176(6):1340-1355

2. Neumann C, Blume J, Roy U, Teh P, Vasanthakumar A, Beller A, Liao Y, Heinrich F, Arenzana TL, Hackney JA, Eidenschenk C, Gálvez EJC, Stehle C, Heinz GA, Maschmeyer P, Sidwell T, Hu Y, Amsen D, Romagnani C, Chang HD, Kruglov A, Mashreghi MF, Shi W, Strowig T, Rutz S*, Kallies A*, Scheffold A*. * (shared authorship) (2019) c-Maf-dependent regulatory T cell control of intestinal Th17 cells and immunoglobulin A establishes host-microbiota homeostasis. Nat. Immunol. 20(4):471-481.

3. Bacher P, Heinrich F, Stervbo U, Nienen N, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A. (2016). Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell. 167(4):1067-1078

4. Bacher P, Steinbach A, Kniemeyer O, Hamprecht A, Assenmacher M, Vehreschild MJ, Vehreschild JJ, Brakhage AA, Cornely OA, Scheffold A. (2015). Fungus-specific CD4+ T cells for rapid identification of invasive pulmonary mold infection. Am J Respir Crit Care Med. 191(3):348-52.

5. De la Rosa M, Rutz S. Dorninger H, Scheffold A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004. 34:2480-8.

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Session 4Simon Fillatreau

“Novel insights into the roles of the adaptive immune system in immune regulation and immune-mediated inflammatory diseases”

Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, AP-HP, Hôpital Necker Enfants Malades, Paris, France

B I O S K E T C H

Our group has a longstanding interest in the role of the adaptive immune system in autoimmune and infectious diseases, which we study using pre-clinical models as well as clinical samples. Our current re-search combines fundamental and translational projects aiming at 1) identifying novel disease-relevant pro- and anti-inflammatory B cell subsets, 2) developing novel therapeutic approaches against immu-ne-mediated diseases harnessing the suppressive functions of B cells or CD4+Foxp3+ T regulatory cells, 3) characterizing the interaction between lymphocytes and microorganisms at the mucosal interface, and its impact on immunological memory. S. Fillatreau studied at Ecole Normale Supérieure de la rue d’Ulm, and did his PhD at the University of Edinburgh. He established the Immune Regulation research group at the Deutsches Rheuma-For-schungszentrum Berlin, a Leibniz Institute, in 2003. In 2015, he became Professor of Immunology at the Medical Faculty of the University Paris Descartes. In 2014, he obtained a European Research Council grant. In 2015, he was awarded the GlaxoSmithKline Stiftung Wissenschaftspreise. In 2016, he was gran-ted a long-term AXA Chair, and appointed as AXA Professor in Translational Immunology. He is editor for the European Journal of Immunology, deputy editor for Cellular Immunology, and review editor for Frontiers in Immunology.

A B S T R A C T

Adaptive lymphocytes are at the core of immune-mediated inflammatory diseases (IMID). The depletion of B cells can have outstanding effects in such diseases, including in those primarily T cell-mediated such as multiple sclerosis (MS). We will discuss how B cells can drive such IMID through the production of pro-inflammatory cytokines, highlighting the B cell subsets involved, and the associated molecular mechanisms. Upon differentiation into antibody-secreting cells (ASC), B cells undergo the remodeling of their cytokine expression profile, and can acquire suppressive functions. We will discuss the capacity of ASC to secrete anti-inflammatory cytokines such as interleukin-10, and to subsequently drive the complete remission from ongoing autoimmune disease. These observations underline an unsuspected diversity within the ASC compartment, and suggest the existence of distinct beneficial versus delete-rious ASC subsets in IMID. This concept is supported by our recent identification of a novel subset of natural regulatory plasma cells expressing LAG-3, PD-L1, and PD-L2. These receptors are also expressed by CD4+ T cells, which play a central role as drivers and regulators of IMID. We will present how enginee-red CD4+Foxp3+ T cells can be used to intercept IMID, and to prevent inadvertent immune reactions associated with the utilization of immune checkpoint inhibitors.


1. Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, Simon Q, Thalmensi J, Baures A, Flühler V, Sakwa I, Stervbo U, Ries S, Jouneau L, Boudinot P, Tsubata T, Adachi T, Hutloff A, Dörner T, Zimber-Strobl U, de Vos AF, Dahlke K, Loh G, Korniotis S, Goosmann C, Weill JC, Reynaud CA, Kauf-mann SHE, Walter J, Fillatreau S. 2018. LAG-3 Inhibitory Receptor Expression Identifies Immunosup-pressive Natural Regulatory Plasma Cells. Immunity. 49 :120-133.

2. Kieback, E., E. Hilgenberg, U. Stervbo, V. Lampropoulou, P. Shen, M. Bunse, Y. Jaimes, P. Boudinot, A. Radbruch, U. Klemm, A.A. Kühl, R. Liblau, N. Hoevelmeyer, S.M. Anderton, W. Uckert, and S. Fillatreau. 2016. Thymus-derived regulatory T cells are positively selected on natural self-antigen through TCR interactions of high functional avidity. Immunity. 44: 1114.

3. Shen, P., Roch, T., V. Lampropoulou, R.A. O’Connor, U. Stervbo, E. Hilgenberg, Y. Jaimes, C. Daridon, R. Lui, L. Jouneau, P. Boudinot, S. Ries, Y. Miyazaki, M.D. Leech, R.C. McPherson, S. Wirtz, M. Neurath, V.D. Dang, K. Hoehlig, E. Meinl, A. Grützkau, J.R. Grün, K. Horn, A.A. Kühl, T. Dörner, A. Bar-or, S.H.E. Kaufmann, S.M. Anderton, and S. Fillatreau. 2014. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 507: 366.

4. Neves, P., V. Lampropoulou, E. Calderon-Gomez, T. Roch, U. Stervbo, P. Shen, A.A. Kuhl, C. Loddenkem-per, M. Haury, S.A. Nedospasov, S.H. Kaufmann, U. Steinhoff, D.P. Calado, and S. Fillatreau. 2010. Sig-naling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity 33:777-790.

5. Fillatreau, S., C.H. Sweenie, M.J. McGeachy, D. Gray, and S.M. Anderton. 2002. B cells regulate au-toimmunity by provision of IL-10. Nat Immunol 3:944-950

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Session 5Eric Vivier

“Harnessing innate immunity in cancer therapy”

Chief Scientific Officer, Head of Innate Pharma Research LaboratoriesProfessor of Immunology, Marseille Medical School and Assistance- Publique des Hôpitaux de Marseille (PU-PH Classe Exceptionnelle)

Head of the “Innate Lymphoid Cell” lab, CIML Head of the immunoprofiling lab, La Timone Hospital, Marseille Co-founder and coordinator of the Federation Hospitalo-Universtaire Marseille-Immunopole | (http://www.marseille-immunopole.org)

B I O S K E T C H

Éric Vivier, DVM, PhD, is Professor of Immunology at Aix-Marseille University and at the Public Hospital of Marseille.Prof. Vivier was appointed Scientific Director of Innate Pharma, a biotechnology company dedicated to improving cancer treatment with innovative therapeutic antibodies that exploit the im-mune system.Eric Vivier is a graduate of the Ecole Nationale Vétérinaire de Maisons-Alfort and received his PhD in Immunology from the University of Paris XI. He completed his post-doctoral training at Harvard Medical School, then joined Aix-Marseille University as professor at the Centre d‘Immunologie de Marseille-Lu-miny (CIML) in 1993 before becoming its director from 2008 to the end of December 2017. He is also one of the founders of Marseille-Immunopôle, an immunology cluster created in 2014 linking fundamental and therapeutic research, innovation and industrial development in the Aix-Marseille re-gion.Eric Vivier‘s work focuses on the functioning of Natural killer lymphocytes (NK) and other innate lym-phoid cells (ILCs). Professor Vivier has published nearly 300 scientific articles and is on the list of the most cited researchers (https://clarivate.com/hcr/ ). Publications: total 360, h-Index: 101, > 38000 citations (See selected publications below)http://scholar.google.fr/citations?user=NlmFOgMAAAAJ&hl=fr&oi=aoA laureate of the European Research Council (ERC advanced grants), a member of the Académie Na-tionale de Médecine and the Institut Universitaire de France, Prof. Vivier has received several awards including those from the Ligue Nationale contre le Cancer (1996, 2004 and 2013) and the European Federation of Immunological Societies (EFIS, 2004).

A B S T R A C T

New therapies promoting antitumor immunity have been recently developed. Most of these immuno-modulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Despite unprecedented successes, only a minority of cancer patients benefit from these treatments, highlighting the need to identify new cells and mole-cules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate

immune responses in immunity, harnessing these responses opens up new possibilities for mounting long-lasting, multilayered tumor control. Along these lines, we will present recent advances on the manipulation of an inhibitory receptor NKG2A or an activating NK cell receptor NKp46 using monoclonal antibodies and multifunctional antibodies respectively, in innovative cancer therapies.


1. Rankin L.C. et al., Complementarity and redundancy of IL-22-producing Innate Lymphoid cells. Na-ture Immunology, 2016, 17: 179-186.

2. Vély F. et al., Evidence of innate lymphoid cell redundancy in humans. Nature Immunology, 2016, 17: 1291-1299.

3. Crinier A. et al., Definition of Natural Killer cell heterogeneity in human and mouse by high-throug-hput single-cell RNA sequencing. Immunity, 2018, 49: 971–986.

4. André P. et al., Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell, 2018, 175: 1731-1743.

5. Gauthier et al. Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tu-mor Immunity. Cell, 2019, doi.org/10.1016/j.cell.2019.04.041

5 S E L E S C T E D R E V I E W S a n d E S S A Y S

1. Vivier E. et al., Innate or adaptive immunity? The example of Natural Killer cells. Science, 2011, 331: 44-49.

2. Pradeu P. & Vivier E. The Discontinuity Theory of Immunity. Science Immunology 2016, 1, aag04793. Ebbo M. et al., Innate lymphoid cells: major players in inflammatory diseases. Nature Reviews

Immunology, 2017, 17 :665–6784. Vivier E et al., Innate Lymphoid Cells: 10 years on. Cell, 2018, 174: 1054-1066.5. Chiossone L. et al., Natural killer cells and other innate lymphoid cells in cancer. Nature Reviews

Immunology, 2018, 18: 671-688.

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Session 5Martin Kriegel

“Suppression of translocating pathobionts in autoimmunity – an interventional paradigm for the future of immunology”

Yale School of Medicine & Roche Innovation CenterNew Haven, USA

B I O S K E T C H

Dr. Kriegel is currently an Associate Professor Adjunct in the Department of Immunobiology at Yale School of Medicine and a Translational Physician Scientist at Roche. His laboratory explores host-micro-biota interactions in autoimmunity and cancer by combining human microbiome studies with gnoto-biotic models. He had completed medical school at the Friedrich-Alexander University of Erlangen-Nuremberg, Ger-many, followed by postdoctoral training as an Emmy-Noether stipendee at Yale with Richard Flavell and at Harvard Medical School with Christophe Benoist and Diane Mathis. Dr. Kriegel has completed residency and rheumatology fellowship at Harvard, before returning to Yale in 2012 as a tenure-track faculty member in the Department of Immunobiology. Dr. Kriegel has received several major foundation awards in the United States as well as national recognitions from the German Society for Endocrinology and the German Society for Rheumatology, respectively. He holds an international patent on targeting gut bacteria in immune diseases and has served as an Advisory Editor for Arthritis & Rheumatology as well as a reviewer for national grant programs in the United States, United Kingdom, Switzerland and Israel.

A B S T R A C T

Despite multiple associations between the microbiome and immune diseases, its role in autoimmunity remains poorly understood. Several mechanisms have recently been uncovered in systemic autoim-munity. These include gut commensal translocation on a cellular level and cross-reactivity as well as post-translational modification of autoantigens on a molecular level. I will focus on the concept of gut barrier leakiness and translocation of live commensals that drive autoimmune pathways in genetically predisposed hosts. The pathobiont E. gallinarum translocates to lymph nodes, liver, and spleen in an autoimmune model to induce autoantigens, endogenous retroviral antigens, Th17/Tfh cells, and auto-antibodies. An intramuscular vaccine against E. gallinarum suppresses translocation and autoimmune pathology, representing a new paradigm for pathobiont-directed therapies. Furthermore, a starch diet suppresses another translocating pathobiont, L. reuteri, that exacerbates the plasmacytoid DC-type I IFN axis in TLR7 transgenic mice. Mechanistically, diet-induced SCFAs tighten TLR7-dependent gut leakiness and suppress growth of L. reuteri in vitro and vivo. In summary, I will cover mechanisms and consequences of pathobiont translocation and outline interventions to suppress pathobionts in order to restore immune homeostasis. Modulation of immunity via the gut microbiota may be an attractive field for interdisciplinary research and the future of immunology in Berlin.


1. Vieira SM, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Kahn N, Costa FRC, Tiniakou E, Grei-ling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA: Transloca-tion of a Gut Pathobiont Drives Autoimmunity in Mice and Humans. Science, 2018; 359:1156-1161.

2. Zegarra-Ruiz D, El Beidaq A, Iniguez, AJ, Lubrano Di Ricco M, Manfredo Vieira S, Ruff WE, Mubiru D, Fine R, Sterpka J, Greiling TM, Dehner C, Kriegel MA: A diet-sensitive commensal Lactobacillus strain mediates TLR7-dependent systemic autoimmunity. Cell Host Microbe, 2019; 25, 113-127.

3. Greiling TM*, Dehner C*, Chen X*, Hughes K, Renfroe SC, Vieira SM, Ruff WE, Boccitto M, Sim S, Kriegel C, Chen X, Girardi M, Degnan P, Goodman AL, Wolin SL#, Kriegel MA#: Commensal Orthologs of the Human Autoantigen Ro60 as Triggers of Autoimmunity in Lupus. Science Translational Medicine, 2018; 10(434). pii: eaan2306.

4. Ruff WE, Dehner C, Kim WJ, Pagovich O, Aguiar CL, Yu AT, Roth AS, Manfredo Vieira, S, Kriegel S, Olamide A, Mulla MJ, Abrahams VM, Kwok WW, Nussinov R, Erkan D, Goodman AL, Kriegel MA: Patho-genic beta2-glycoprotein I autoreactive T and B cells cross-react with non-orthologous mimotopes expressed by a common human gut commensal. Cell Host Microbe, 2019; 26: 100-113.

5. Fine R, Vieira SM, Gilmore MS, Kriegel MA: Mechanisms and Consequences of Gut Commensal Trans-location in Chronic Diseases. Gut Microbes, 2019, DOI: 10.1080/19490976.2019.1629236.

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Session 5Manolis Pasparakis

“The intimate connection between cell death and inflammation”

Institute for Genetics and CECAD Research Center, University of Cologne, Germany

B I O S K E T C H

Manolis Pasparakis is interested to understand the mechanisms regulating inflammation and the pa-thogenesis of inflammatory diseases and cancer. A topic of particular interest in the Pasparakis’ lab is the function of different pathways of regulated cell death, including necroptosis, pyroptosis and apoptosis, in immunity and inflammation and the underlying mechanisms.Manolis Pasparakis received his bachelor’s and Ph.D. degrees in biology from the University of Athens, Greece. After postdoctoral training in the Institute for Genetics of the University of Cologne he started his independent research as a group leader at the Mouse Biology Programme of EMBL in Monterotondo, Italy. He became Professor at the Institute for Genetics of the University of Cologne in 2005, where he works since then.

A B S T R A C T

Cell death is recognized for many years as an important biological process for the maintenance of tissue homeostasis as well as for pathogen defense. Until recently, cell death was synonymous to apop-tosis. However, the recent discoveries of molecularly controlled pathways of lytic cell death, such as necroptosis and pyroptosis, broadened the scope of cell death research from a predominantly apop-tosis-centric view to a wider exploration of the regulation and function of the different types of cell death. A key question that has emerged is: “why are there so many forms of cell death?” It is now generally accepted that the consequences of cell death at the level of the tissue and the organism are profoundly affected by the way a cell dies and that cell death is a central component of immunity. The currently prevailing concept is that specific types of cell death potently activate immune responses, although the underlying mechanisms remain poorly understood. A number of studies in genetic mouse models have provided experimental evidence that cell death induces inflammation in vivo, suggesting that cell death could contribute to the pathogenesis of inflammatory diseases. I will discuss our recent studies on the role of cell death in inflammation and the underlying mechanisms.

5 M O S T I M P O R T A N T P U B L I C A T I O N S

1. Polykratis A, Martens A, Eren RO, Shirasaki Y, Yamagichi M, Yamaguchi Y, Uemura S, Miura M, Holz-mann B, Kollias G, Armaka M, van Loo G, Pasparakis, M. (2019) A20 prevents inflammasome-depen-dent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin binding domain. Nat. Cell Biol. 21, 731-742.

2. Lin, J., Kumari, S., Kim, C., Van, T.-M., Wachsmuth, L., Polykratis, A., and Pasparakis, M. (2016). RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540, 124-128.

3. Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, T., Hermance, N., Zelic, M., Kirsch, P., Basic, M., Bleich, A., Kelliher, M., and Pasparakis, M. (2014). RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94.

4. Welz, P.S., Wullaert, A., Vlantis, K., Kondylis, V., Fernandez-Majada, V., Ermolaeva, M., Kirsch, P., Ster-ner-Kock, A., van Loo, G., and Pasparakis, M. (2011). FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330-334.

5. Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M.F., and Pasparakis, M. (2007). Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561.

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Session 5Katja Simon

“Autophagy and Proteostasis in Immune Senescence”

Kennedy Institute of RheumatologyUniversity of Oxford

B I O S K E T C H

As a principal investigator in Oxford, she set up an independent line of enquiry investigating autophagy in immunopoeisis. Her group discovered that autophagy, the main conserved cellular bulk degradation pathway, maintains healthy red blood cells, stem cells and memory T cells. It promotes differentiation and prevents ageing of immune cells. She received the 2018 Ita Askonas prize for outstanding achie-vements as a female European group leader. She is a Wellcome investigator.Katja Simon is Professor at Oxford University (UK) and principal investigator at the Kennedy Institute of Rheumatology, studying cell fates in the hematopoietic system. She trained as an Immunologist under Avrion Mitchison, first director of the DRFZ Berlin, and found that TH1 cytokines are found in excess in the human autoimmune disease rheumatoid arthritis (she received the EULAR Award in 1994). As a post-doc at the Centre d’Immunologie Marseille Luminy, she investigated transcription factors regulating thymic cell death. During her second postdoc in Oxford she pursued her interest in cell death molecules in thymic selection, inflammation and tumour immunity.

A B S T R A C T

With increasing life expectancy, the number of people over 60 years is expected to double by 2050, reaching 2.1 billion worldwide. The severity of many infections increases substantially with age, and the success of childhood vaccination is widely recognized but the importance of vaccination of the elderly population is frequently underestimated. Vaccines are known to be particularly ineffective in the elder-ly, yet some vaccines such as influenza are primarily given to that age group. Immune senescence is characterized by a decline in innate and adaptive immunity together with an increase in low-grade chronic inflammation contributing to age-related diseases such as osteoarthri-tis, cardiovascular and neurodegenerative diseases. Reversing or halting immune ageing would open opportunities to improve management of age-related morbidities and have a major impact on the health of our society. The discovery of autophagy-related proteins greatly advanced the mechanistic understanding of autophagy. We showed that autophagy prevents immune aging. In this lecture, I will present our most recent data of a novel pathway relying on autophagy’s potential to improve human vaccination of the elderly. I will discuss the translational regulation of autophagy that controls proteostasis in long- lived T and B lymphocytes and novel ways to reverse immune sene-scence


1. Puleston, D.J., H. Zhang, T.J. Powell, E. Lipina, S. Sims, I. Panse, A.S. Watson, V. Cerundolo, A.R. Town-send, P. Klenerman, and A.K. Simon, Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife, 2014. 3.

2. Riffelmacher, T., A. Clarke, F.C. Richter, A. Stranks, S. Pandey, S. Danielli, P. Hublitz, Z.R. Yu, E. Johnson, T. Schwerd, J. McCullagh, H. Uhlig, S.E.W. Jacobsen, and A.K. Simon, Autophagy-Dependent Gene-ration of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity, 2017. 47(3): p. 466-480

3. Clarke, A.J., T. Riffelmacher, D. Braas, R.J. Cornall, and A.K. Simon, B1a B cells require autophagy for metabolic homeostasis and self-renewal. J Exp Med, 2018. 215(2): p. 399-413.

4. Clarke, A.J. and Simon, A.K. Autophagy in the renewal, differentiation and homeostasis of immune cells, Nature Reviews Immunology, 2018, 19 (3): p. 170-183

5. Zhang, H., Alsaleh, G., Feltham, J., Sun, Y., Riffelmacher, T., Charles, P., Frau, L., Yu, Z., Mohammed, S., Balabanov, S., Mellor, J. and Simon, A.K., Translational control of TFEB and autophagy via eIF5A rejuvenates B cell immunity. Molecular Cell, August 26, 2019

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Session 6Thomas Blankenstein

“T-Immunology”

Institute of Immunology, Charite, Campus Buch andMax-Delbrück Center for Molecular Medicine

B I O S K E T C H

Thomas Blankenstein works on several aspects of cancer immunology, with special focus on the de-velopment of cancer models that better resemble human cancer, the role of the tumor stroma for tumor progression and as target for immunotherapy, and the development of strategies for convenient and effective T-cell therapy. Thomas Blankenstein is research group leader at the Max Delbrück Center for Molecular Medicine (since 1993) and Director of the Institute of Immunology at the Charite in Berlin, Germany (since 2000). He received his Ph.D. from the Institute of Immunology in Cologne, Germany in 1987. He joined the Institute of Immunology of the Free University of Berlin in 1988 and was visiting scientist in the Department of Pathology, University of Chicago, in 1991. From 2006-2018 he was spokesman of Collaborative Research Center (Sonderforschungsbereich TR36) on ‘Adoptive T cell therapy’.

A B S T R A C T

We generated mice harboring the human gene loci encoding unrearranged TCRα and TCRβ V-(D)-J-C genes, both around 1 megabase in size. By crossing with respective mouse lines, mouse TCRα and TCRβ gene loci were inactivated, as well as mouse MHC I genes, and human MHC I gene was introduced. These mice express a diverse T cell repertoire, are not tolerant for many human tumor-associated antigens (epitopes) and allow isolation of human TCR, which do not exist in the human repertoire or only at exceedingly low frequencies. They proved useful to isolate human TCRs of higher functional activity compared to those isolated from humans.


1. Blankenstein T, Bonhomme F and Krawinkel U (1987). Evolution of pseudogenes in the immunoglo-bulin VH-gene family of the mouse. Immunogenetics 26: 237-248.

2. Hock H, Dorsch M, Kunzendorf U, Überla K, Qin Z, Diamantstein T and Blankenstein T (1993). Vaccinations with tumor cells genetically engineered to produce different cytokines: effectivity not superior to a classical adjuvant. Cancer Res 53: 714-716.

3. Schüler T and Blankenstein T (2003). CD8 effector T cells reject tumors by direct antigen recognition but indirect action on host cells. J Immunol 170: 4427-4431.

4. Qin Z, Schwartzkopff J, Pradera F, Kammertöns T, Seliger B, Pircher H and Blankenstein T (2003). A critical requirement of IFNγ-mediated angiostasis for tumor rejection by CD8 T cells. Cancer Res 63: 4095-4100.

5. Qin Z and Blankenstein T (2004). A cancer immunosurveillance controversy. Nat Immunol 5: 3-4.

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Session 6Gerald Willimsky

“Oncogene-specific T cells at work: in experimental models and in translation”

Experimental and Translational Cancer ImmunologyInstitute of Immunology (Charité - Universitätsmedizin Berlin)and German Cancer Research Center (DKFZ Heidelberg)

B I O S K E T C H

Cancer cells can be recognized by T cells, the success story of checkpoint inhibitors has reinforced this notion. To study the spontaneous and therapy-induced immune response against non-transplanted cancers mice with conditional oncogene-driven cancer development have been analyzed. In order to test the efficiency of T cell receptor (TCR) gene-modified T cells in vivo in a clinically relevant context these autochthonous cancer models are further developed with therapeutically relevant cancer-speci-fic antigens, e.g. using in vivo CRISPR/Cas system. This also includes the identification of relevant hu-man immunogenic cancer rejection antigens as well as generation of human TCRs with optimal affinity. Suitable TCRs will be pursued into clinical application, accompanied with exploration of the feasibility of non-viral CRISPR T cell engineering.

since 2016 Joint DKTK-Professorship for Experimental and Translational Cancer Immunology, Charité - Universitätsmedizin Berlin and German Cancer Research Center, Heidelberg2000-2015 Research Group Leader at Charité - Universitätsmedizin Berlin, Institute of Immunology1996-2000 Staff Scientist at the Max-Delbrück-Center of Molecular Medicine, Berlin1994-1996 Postdoctoral Scientist at the Max-Delbrück-Center of Molecular Medicine, Berlin1994-1996 Postdoctoral Scientist at ´Institut für Genbiologische Forschung´, Berlin1985-1993 Studies of Chemistry/Biochemistry; Technical University Berlin, Philipps-University Marburg, PhD-Thesis 1993

A B S T R A C T

To this end sporadic and virus-induced cancer development using conditional oncogene (SV40 large T-antigen, TAg) expression have shown profound cancer-induced systemic tolerance already at the premalignant stage of sporadic cancers on the one hand and induction of systemic immunity but local antigen specific cytotoxic T cell (CTL) tolerance in virus-induced cancers on the other hand. To analyze the interaction between (pre-)malignant B cells and T cells, we generated transgenic mice that allow B cell-specific TAg induction. Constitutive TAg expression in CD19+ cells resulted in TAg-tolerant CD8+ T cells early in life and development of B cell lymphomas. In contrast, when TAg was induced in B cells of adult mice that had retained TAg-competent CD8+ T cells, lymphoma formation was exceptionally rare late in life. Here, increased lymphoma incidence in the absence of TAg-specific T cells suggested T cell-mediated inhibition of lymphoma progression.

In the course of analyzing the human mutanome-encoded repertoire of tumor-specific T cell epitopes through the isolation of neoantigen-specific T cell receptors (TCRs) we identified a number of immuno-genic neoepitopes derived from recurrent activating mutations. Currently, their potential for proof of concept clinical testing, e.g. utilizing TCRs targeting mutations in the GTPases of the Rac family, is analyzed.


1. Hoser D, Schön C, Loddenkemper C, Lohneis P, Kühl AA, Sommermann T, Blankenstein T, Willimsky G. 2018. Oncogene-specific T cells fail to eradicate lymphoma-initiating B cells in mice. Blood 132: 924.

2. Schmidt K, Keller C, Kühl AA, Textor A, Seifert U, Blankenstein T, Willimsky* G, Kloetzel* PM. 2018. ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T-cell therapy in mice. Cancer Res 78: 3243. *Contributed equally.

3. Schmidt K, Zilio S, Schmollinger JC, Bronte V, Blankenstein T, and Willimsky G. 2013. Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer. Blood 121:1740.

4. Willimsky G, Schmidt K, Loddenkemper C, Gellermann J, and Blankenstein T. 2013. Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance. J Clin Invest 123: 1032.

5. Willimsky, G, Blankenstein T. 2005. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437:141.

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Session 6Andrea Schietinger

“Molecular and epigenetic programs defining tumor-specific T cell differentiation”

Andrea Schietinger, PhDImmunology Program | Memorial Sloan Kettering Cancer CenterNew York, USA

B I O S K E T C H

Dr. Andrea Schietinger is an Assistant Member in the Immunology Program at Memorial Sloan Kettering Cancer Center (MSKCC), and Assistant Professor at Weill Cornell Medical College in New York since 2015. Her laboratory studies the molecular and epigenetic mechanisms underlying T cell differentiation and dysfunction in the context of self-tolerance, autoimmunity and tumors (Nature 2017; Nature 2019).

After receiving her degree in Pharmacology from the University of Hamburg in 2001, she enrolled in a joint PhD program between the Ludwig Maximilian University of Munich (LMU) and The University of Chicago (UofC). During her PhD she worked in Dr. Hans Schreiber’s laboratory at the UofC, where she studied how aberrant posttranslational glycosylation of wildtype proteins in cancer cells creates tumor-specific neo-antigens (Science, 2006); she received her PhD in 2007 from the LMU. As a postdoc-toral fellow in Dr. Philip Greenberg’s lab at the University of Washington in Seattle, she investigated the transcriptional programs needed for self-reactive T cells to maintain peripheral self-tolerance (Science, 2012). Dr. Schietinger is the recipient of numerous awards and grants, including the NIH Director‘s New Innovator Award in 2017, and the Lloyd Old STAR Award from the Cancer Research Institute in 2019.

A B S T R A C T

T cell responses to cancers differ depending on the nature of the target antigen: tumor antigens that are self-proteins are generally weakly immunogenic due to pre-existing self-tolerance, whereas tumor antigens that are tumor-specific (e.g. mutated proteins) are potentially highly immunogenic because the immune system has not been exposed to these antigens. We recently demonstrated that tumor-spe-cific T cells differentiate to a non-responsive state following initial encounter with tumor antigen, even before the emergence of a pathologically-defined tumor. While this state is initially reversible, it pro-gresses to a fixed state that cannot be rescued, and the reversible and fixed non-responsive states were defined by discrete chromatin states. This pathway resembles what we observe in peripheral self-tolerance in which self-reactive T cells differentiate to an epigenetically-encoded tolerant state after encountering self-antigen. Thus, the ad-aptive immune system is under strong pressure to permanently neutralize self-reactive T cells through a specific, epigenetically-enforced differentiation program, and while this differentiation pathway ef-fectively prevents autoimmunity for the most part, unfortunately, it just as effectively subverts tu-mor-specific anti-cancer responses. New insights into the epigenetic and molecular programs under-lying hyporesponsiveness in tumor-specific T cells will be discussed.


1. Scott AC, Dündar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, Trivedi P, Menocal L, Appleby H, Camara S, Zamarin D, Walther T, Snyder A, Femia MR, Comen EA, Wen HY, Hellmann MD, Anandasabapathy N, Liu Y, Altorki NK, Lauer P, Levy O, Glickman MS, Kaye J, Betel D, Philip M, Schietinger A.

“TOX is a critical regulator of tumour-specific T cell differentiation.” Nature 2019; 571(7764):270-274.

2. Philip M, Fairchild L, Sun L, Horste E, Camara S, Shakiba M, Scott AC, Viale A, Lauer P, Merghoub T, Hellmann M, Wolchok JD, Leslie CL, Schietinger A.

“Discrete chromatin states define tumor-specific T cell dysfunction and therapeutic reprogramma-bility.”

Nature 2017; 545(7655):452-456.

3. Schietinger A, Philip M, Krisnawan VE, Chiu EY, Delrow JJ, Basom RS, Lauer P, Brockstedt DG, Knob-laugh SE, Hämmerling GJ, Schell TD, Garbi N, Greenberg PD. “Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis.”

Immunity 2016; 45(2):389-401.

4. Schietinger A, Delrow J, Basom R, Blattman JN, Greenberg PD. “Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state.” Science 2012; 335(6069): 723-7.

5. Schietinger A, Philip M, Yoshida BA, Azadi P, Liu H, Meredith SC, Schreiber H. “A mutant chaperone converts a wild-type protein into a tumor-specific antigen.” Science 2006; 314(5797): 304-308.

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Session 6Mathias Heikenwälder

“On the role of immune cells on NASH/liver cancer and its consequences for therapy”

Department Chronic Inflammation and Cancer, German Cancer research center (DKFZ), Heidelberg, Germany.

B I O S K E T C H

Since October 2015 I am heading the department “Chronic Inflammation and Cancer” at the German Cancer Research Center (DKFZ). My laboratory aims at investigating chronic inflammatory diseases driving tissue-damage (e.g. dietary-, virally-induced), autoimmunity and cancer, with focus on hepato-biliary/gastrointestinal diseases. We aim at understanding the systemic effects of pathologies and the interplay between non-lymphoid tissues, the hepatobiliary tract and the immune system (e.g. liver-gut axis). We focus on functional, comparative studies using human patient-derived tissue, animal models and perform pre-clincial/clinical trials. After my studies of genetics/microbiology at the Max-Perutz laboratories (MPL)/institute of molecular pathology (IMP), Vienna, I completed my master at the Max-Delbrück Center (MDC), Berlin. Thereafter, I performed my Ph.D. at the University Hospital Zurich (USZ; institute of neuropathology) in the field of neuroinflammation/neurodegeneration. After 2 years post-doc with own funding at the department of pathology, USZ, I became Prof. Max-Cloëtta-fellow and independent PI, focusing on inflammation-in-duced tissue damage. After my habilitation at the medical faculty, USZ, I became a Hofschneider Pro-fessor (W2)/Helmholtz Young Group Investigator (HYGI) at the institute of virology, Klinikum Rechts der Isar (MRI)/Helmholtz Zentrum für Gesundheit und Umwelt (HMGU), Munich, focusing on the link between chronic inflammation, tissue damage, autoimmunity and cancer in 2010.

A B S T R A C T

Chronic hepatitis is the main driver of liver-cancer, the third most common cause for cancer-related death in humans. Different etiologies cause chronic hepatitis and cancer: Chronic viral infections with Hepatitis B or C viruses (HBV, HCV), chronic alcohol abuse or chronic high-caloric diet in combination with sedentary life-style. Due to consumption of high-caloric food combined with increased sedentary life-style, overweight, metabolic syndrome and obesity incidence has grown rapidly in Western (e.g. USA) but also in developing countries (e.g. India), affecting adults and children. Although chronic viral infections are still the leading cause for liver-cancer, alcoholic steatohepatitis (ASH), non-alcoholic fatty liver (NAFL) and subsequent non-alcoholic steatohepatitis (NASH) have become important etiolo-gies for liver-cancer. We have generated several pre-clinical mouse models to study the mechanisms of inflammation-induced liver-cancer in the context of a metabolic syndrome. These models recapitulate several human pathophysiological hallmarks of NASH/ASH induced liver-cancer. Adaptive but also in-nate immune cells play an important role in driving NASH and subsequent HCC and - at the same time - contribute to tumor surveillance efficacy. Here, I will report on the interplay between different types of immune cells driving NASH and liver-can-cer and how this affects anti-tumor therapy strategies.


1. O’Connor T, Zhou X, Kosla J, Adili A, Garcia-Beccaria M, Kotsiliti E, Pfister D, Johlke AL, Sinha A, San-kowski R, Schick M, Lewis R, Dokalis N, Seubert B, Höchst B, Inverso D, Heide D, Zhang W, Weihrich P, Manske K, Wohlleber D, Anton M, Höllein A, Seleznik G, Bremer J, Bleul S, Augustin H, Scherer F, Ködel U, Weber A, Protzer U, Förster R, Wirth T, Aguzzi A, Meissner F, Prinz M, Baumann B, Höpken UE, Knolle P, von Baumgarten L, Keller U, Heikenwalder M. “Age-related gliosis promotes central nervous system lymphoma metastasis through CCL19-mediated tumor cell retention”.

Cancer Cell. 2019 Sep; 36, 1-18 September 16, 2019.

2. Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O‘Connor T, Weston CJ, Adams DH, Sheriff L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, Gawaz M, Weber A. and Heikenwalder M. „Platelet GPIba is a mediator and potential interventional target for NASH and subsequent liver cancer.”

Nature Medicine. 2019 Apr;25(4):641-655. doi: 10.1038/s41591-019-0379-5. Epub 2019 Apr 1.

3. Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Öllinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Höchst B, Wohlleber D, Jörs S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Hüser N, Davis RJ, Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder M. “Kupffer-cell derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS”.

Cancer Cell. 2017, 31:771-789.

4. Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, Ringelhan M, Simonavicius N, Egger M, Wohlleber D, Lorentzen A, Einer C, Schulz S, Clavel T, Protzer U, Thiele C, Zischka H, Moch H, Tschöp M, Tumanov AV, Haller D, Unger K, Karin M, Kopf M, Knolle P, Weber A°, Heikenwalder M°. “Metabolic activation of intrahepatic CD8+ T-cells and NKT-cells causes nonalcoholic steatohepatitis and hepa-tocellular carcinoma via cross-talk with hepatocytes”.

Cancer Cell. 2014, 26:549-564.

5. Wolf MJ, Hoos A, Bauer J, Boettcher S, Knust M, Weber A, Simonavicius N, Schneider C, Lang M, Stürzl M, Croner RS, Konrad A, Manz MG, Moch H, Aguzzi A, van Loo G, Pasparakis M, Prinz M, Borsig L, Hei-kenwalder M. “Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway”.

Cancer Cell. 2012, 22:91-105.

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Session 6Florian Greten

“The inflammatory tumor microenvironment”

1Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main 2Frankfurt Cancer Institute, Goethe University Frankfurt

B I O S K E T C H

Florian R. Greten is Chair of Tumor Biology at the Goethe University Frankfurt and Director of Institute of Tumor Biology and Experimental Therapy, Georg-Speyer-Haus since August 2013. He is a founder of the newly established Frankfurt Cancer Institute (FCI) and acts as Speaker of the LOEWE-Center Frankfurt Cancer Institute since 01/2019. From 2010-2013 he was Professor of Molecular Gastrointestinal Oncology (W2) at the Klinikum rechts der Isar, Technical University Munich and prior to that Emmy-Noether Group Leader and Resident in Internal Medicine, Dept. of Gastroenterology at the Klinikum rechts der Isar, Technical University Munich. From 2001-2004 he performed his Post-Doctoral Studies with Michael Karin at the University of California, San Diego. He started his internship in Internal Medicine in 1998 at the Dept. of Medicine, University of Ulm after completing his Medical Studies at the University of Hamburg and Vienna. Currently, he acts as speaker of the DFG Research Unit 2438 ‘Cell Plasticity in Colorectal Carcinogenesis’, Deputy Head of the Board of Trustees of the Paul Ehrlich Foundation, member of the DFG committee ‘Hinterzartener Kreis für Krebsforschung’ and since 2019 he is the Head of the Grants Committee “Clinical and Basic Research” of the Deutsche Krebshilfe (German Cancer Aid).

A B S T R A C T

The tumor microenvironment is composed of different cells that can be grouped into three classes: cancer-associated fibroblasts, vascular cells and infiltrating immune cells. The relative abundance of these respective cell types as well as their polarization profile can greatly vary and often predicts pro-gnosis and response to therapy. Cells of all three groups can control tumor cell proliferation, cell death, growth suppressor evasion, energy metabolism, angiogenesis, immune evasion as well as invasion in a non-autonomous manner. Thus, it has become unequivocally evident that tumor development depends on the intricate reciprocal interplay of mutagenized tumor cells with their local and distant microen-vironment. Cytokines and other signal proteins control the plasticity of stromal, tumor and cancer stem like cells in an autocrine and paracrine manner thereby shaping the complex cellular contexture, which ultimately forms a pro- or anti-tumorigenic milieu. A detailed understanding of the cellular and molecular mechanisms underlying these complex interactions of tumor, stroma and immune cells may help to identify novel therapeutic targets. We recently identified signaling pathways during early and late tumorigenesis that highlight the importance of tumor cells for T cell polarization and suppression of adaptive immunity and that help to understand why stroma-rich colon tumors may be associated with a worse prognosis.

5 M O S T I M P O R T A N T P U B L I C A T I O N S

1. Greten, FR, Grivennikov, SI: Inflammation and Cancer: Triggers, Mechanisms and Consequences. Immunity. 2019 Jul 16;51(1):27-41

2. Ziegler, PK, Bollrath, J, Pallangyo, CK, Matsutani, T, Canli, Ö, DeOliveira, T, Diamanti, MA, Müller, N, Gamrekelashvili, Putoczki, T, Horst, D, Mankan, AK, Öner, MG, Müller, S, Müller-Höcker, J, Kirchner, T, Slotta-Huspenina, J, Taketo, MM, Reinheckel, T, Dröse, S, Larner, AC, Wels, WS, Ernst, M, Greten, TF, Arkan, MC, Korn, T, Wirth, D, Greten, FR.: Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorgenesis. Cell. 2018 Jun 28;174(1):88-101

3. Varga, J., Greten FR.: Cell Plasticity in Epithelial Homeostasis and Tumorigenesis. Nat Cell Biol. 2017, 19:1133-1141

4. Canli Ö, Adele M Nicolas, Gupta J, Finkelmeier F, Olga Goncharova, Pesic M, Tobias Neumann, Horst D, Löwer M, Sahin U, Greten FR. Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis. Cancer Cell, 2017, 32:869-883.

5. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Hejimans J, Huels DJ, Moreaux G, Rupec RA, Gerhard M, Schmid R, Barker N, Clevers H, Lang R, Neumann, J, Kirch-ner T, Taketo MM, van den Brink GR, Sansom OJ, Arkan MC, and Greten FR. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell like properties. Cell 2013; 152:25-38.

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Session 7Norbert Suttorp

“Host directed approaches to diagnostics, treatment and prevention of infectious diseases” part I

Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin

B I O S K E T C H

• StudyofmedicineinMünsteranGiessen.Post-doc-timeatStanforduniversityanduniversity of Giessen.

• FullC4-Professor,ChairmanandDirector,Dept.ofInternalMedicine/InfectiousDiseasesand Respiratory Medicine, Charité, Berlin (since 1999).

• SpeakerofDFG-fundedcollaborativeresearchcenter(CRC)SFB/TR-84(innateimmunityofthelung) (since 2010)

• SpeakerofBMBF-fundedPROGRESS(susceptibilitytoinfection)(since2007)

• MemberofAdvisoryBoardoftheGermanMedicalAssociation(since2003)

• SpeakerofBMBF-fundedcompetencenetworkCAPNETZ(com.acq.pneumonia)(2002-2012).

• MemberoftheGermanNationalAcademyofScience-Leopoldina(since2000)

A B S T R A C T

My major interest relates to innate immunity of the lung in the context of infection, inflammation, resolution and repair of lung tissue. Hereby we focus on macrophage- and PMN-biology. Mechanisms of endothelial lung barrier failure are a further focus of our work. The intention is to apply host directed therapies to improve pneumonia outcome and to design therapies that go beyond antibiotics. In a more clinical approach we identified new biomarkers for disease severity using genotyping, tran-scriptomics and proteomics in well characterized patient cohorts with pneumonia. Finally we apply methods of system medicine in pneumonia to model an infection of the lung tissue (CAPSyS-project).


1. Maschirow L, Suttorp N, Opitz B. Microbiota-Dependent Regulation of Antimicrobial Immunity in the Lung. Am J Respir Cell Mol Biol. 2019; 61:284-289.

2. Robak OH, Heimesaat MM, Kruglov AA, Prepens S, Ninnemann J, Gutbier B, Reppe K, Hochrein H, Su-ter M, Kirschning CJ, Marathe V, Buer J, Hornef MW, Schnare M, Schneider P, Witzenrath M, Bereswill S, Steinhoff U, Suttorp N, Sander LE, Chaput C, Opitz B. Antibiotic treatment-induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia. J Clin Invest. 2018; 128:3535-3545.

3. Rabes A, Suttorp N, Opitz B. Inflammasomes in Pneumococcal Infection: Innate Immune Sensing and Bacterial Evasion Strategies. Curr Top Microbiol Immunol. 2016; 397:215-27.

4. Tabeling C, Yu H, Wang L, Ranke H, Goldenberg NM, Zabini D, Noe E, Krauszman A, Gutbier B, Yin J, Schaefer M, Arenz C, Hocke AC, Suttorp N, Proia RL, Witzenrath M, Kuebler WM. CFTR and sphingoli-pids mediate hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci U S A. 2015;112:E1614-23. doi: 10.1073/pnas.1421190112.

5. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006, 12(2):

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Session 7Leif-Erik Sander

“Host directed approaches to diagnostics, treatment and prevention of infectious diseases” part II

Department of Infectious Diseases and Respiratory MedicineCharité – Universitätsmedizin Berlin

B I O S K E T C H

Leif Erik Sander is a clinician scientist specializing in internal medicine, pulmonology and infectious diseases. His research is focused on dissecting mechanisms of infection and vaccination, and on the development of novel immunization strategies against the growing threat of multi-drug resistant in-fections. His work has revealed an inherent capacity of the immune system to detect microbial viability, which appears to be a central driver in immunity to infections and vaccination.A graduate of the Hannover Medical School, he defended his dissertation in 2006. Following his clinical residency in the Dept. of Medicine at the University Hospital Aachen, he received a DFG fellowship to perform his postdoctoral training in the laboratory of Julie Blander at the Mount Sinai School of Me-dicine in New York, NY in 2008. In 2012, he was accepted to the Emmy Noether Program of the DFG and established his research group at the Dept. of Infectious Diseases and Respiratory Medicine at Charité. He has received several awards, including the ‘Theodor Frerichs Preis’ of the German Society of Inter-nal Medicine (DGIM). He is a clinical consultant, and in 2016, he was named W2 Professor of Infectious Diseases, Immunology and Vaccinology at Charité.

A B S T R A C T

Vaccines represent arguably one of the most effective public health interventions of all times. Des-pite the long-standing success, many principles of vaccination remain incompletely understood. For instance, the widely-observed qualitative difference in the immune responses to live and non-live vaccines is still largely unexplained. Live attenuated vaccines (LAVs) often induce life-long protective immunity following a single immunization, which is rarely achieved with non-live vaccine preparations. By virtue of their microbial origin, LAVs contain natural ligands (PAMPs) and exert inherent adjuvant activity. We have previously demonstrated that antigen presenting cells (APCs) distinguish live from inanimate microbial matter via recognition of conserved viability-associated molecular signals, so-cal-led ‘vita-PAMPs’. We have identifi ed the detection of microbial viability by APCs as a potent driver of T follicular helper cell differentiation and vaccine responses in humans and pigs. Yet, despite the apparent relevance of innate immune signals in vaccine responses, relatively little is known about the interaction of common LAVs, like the measles vaccine, with the innate immune system. I will present recent insights into the human immune response to LAVs and I will discuss our vision of developing vaccines that combine the unrivalled effi cacy of LAVs with the superior safety profi le and convenience of modern subunit vaccines.


1. Georg P, Sander LE. Innate sensors that control vaccine responses. Curr Opin Immunol 2019;59:31-41

2. Ugolini M*, Gerhard J*, Burkert S*, Jensen KJ, Georg P, Ebner F, Volkers S, Thada S, Dietert K, Bauer L, Schäfer A, Helbig ET, Opitz B, Kurth F, Sur S, Dittrich N, Gaddam S, Conrad ML, Benn CS, Blohm U, Gruber AD, Hutloff A, Hartmann S, Boekschoten MV, Müller M, Jungersen G, Schumann RR, Suttorp N, Sander LE. Recognition of microbial viability via TLR8 promotes T follicular helper cell differentia-tion and vaccine responses. Nat Immunol 2018;19:386-96

3. Garaude J, Acín-Pérez R, Martínez-Cano S, Enamorado M, Ugolini M, Nistal-Villán E, Hervás-Stubbs S, Pelegrín P, Sander LE, Enríquez JA, Sancho D. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense. Nat Immunol 2016;17:1037-1045

4. Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Müller M, Blander JM. Detection of prokaryotic mRNA signifi es microbial viability and promotes immunity. Nature 2011 474:385-9

5. Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Müller M, Blander JM, Tacke F, Trautwein C: Hepatic Acute Phase Proteins Control Innate Immune Responses During Infection by Promoting Myeloid Derived Suppressor Cell Function. J Exp Med 2010; 207(7):1453-64

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Session 7Susanne Herold

“Macrophages – key effector cells in organ damage and injury resolution in the infected lung”

Universities of Giessen & Marburg Lung Center, German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute Department of Medicine II | Klinikstr. 33, 35390 Giessen, Germany

B I O S K E T C H

My research addresses the molecular mechanisms of phagocyte-epithelial cell interactions during pa-thogen-induced lung injury regarding host defense, epithelial barrier function, and stem cell niche-me-diated tissue regeneration, with a focus on influenza virus and bacterial pneumonia. My projects aim at defining novel therapeutic targets for treatment to attenuate lung injury and to foster organ regenera-tion in severe lung infection in a translational bench-to-bedside approach. I received an MD title (Dr. med.) in 2003 and followed a clinician-scientist career path as member of the International Graduate Program “Molecular Biology and Medicine of the Lung” where I graduated with a PhD title in 2008 at the Justus-Liebig University. I got board-certified in Internal Medicine, Infectious Diseases and Pulmonary Medicine. Since 2013 I am an Adjunct Professor at Northwestern University, Feinberg School of Medicine (Division of Pulmonary and Critical Care Medicine), became DZL W2 Pro-fessor for Acute Lung Injury at the JLU Giessen in 2015, and W3 Professor for Pulmonary Infections in 2018, the latter associated with the Coordinator Position of the DFG-funded Clinical Research Unit 309 “Virus-induced Lung Injury” (KFO309) and the Clinical Section Chair for Infectious Diseases at the De-partment of Medicine II. I am currently the Co-Speaker of the Berlin-Giessen SFB TR84 “Innate Immunity of the Lung” and Steering Member of the DFG-funded Clinician-Scientist Program “JLU-CAREER”.

A B S T R A C T

Lung macrophages are a heterogeneous cell population well-known to set up the first line of defen-se against invading pathogens, but also increasingly recognized to be involved in lung homeostatic and regenerative processes based on their functional plasticity. Tissue-resident alveolar macrophages (TR-AM) derive from yolk-sac progenitors, seed the organ early during embryogenesis and self-renew locally during homeostasis in presence of GM-CSF, which also significantly increases their host defense capacity. In contrast, their circulating counterparts, bone marrow-derived (inflammatory) macropha-ges (BMDM), are readily recruited to the site of infection or injury and gradually replace the TR-AM niche when depleted during infection, but might also cause substantial epithelial injury via release of pro-apoptotic factors like TRAIL. The spatiotemporal appearance of BMDM in the lung upon an infectious insult occurs in a highly coor-dinated manner. BMDM are subjected to extensive transcriptional and metabolic reprogramming by al-veolar microenvironmental signals that shape their fate and function, i.e. their anti-pathogen defense potential versus their tissue-protective/regenerative profile and their capacity to replenish the TR-AM niche. Transcriptome profiling combined with functional analyses using organoid modeling and adop-tive intrapulmonary transfer of highly purified BMDM phenotypes confirmed that BMDM have diverse gene expression profiles associated with defined functional phenotypes. We identified key programs

and BMDM-expressed effector molecules which seem to be directly involved in epithelial regeneration orchestrated within distinct stem cell niches of the lung in the later stage of infection. Ultimately, such effector molecules when therapeutically applied to pneumonic mice substantially increased their sur-vival, highlighting the putative translational relevance of these findings.


1. Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Schmoldt C, Bespalowa J, Vadasz I, Morty RE, Wolff T, Pleschka S, Gattenloehner S, Fink L, Mayer K, Lohmeyer J, Seeger W, Sznajder JI, Mutlu GM, Budinger GRS, Herold S. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. J Clin Invest 126(4):1566-80, 2016.

2. Herold S, Hoegner K, Vadász I, Gessler T, Wilhelm J, Mayer K, Morty RE, Walmrath HD, Seeger W, Lohmeyer J. Inhaled GM-CSF as treatment of pneumonia-associated acute respiratory distress syn-drome. Am J Respir Crit Care Med. 189(5):609-11, 2014.

3. Unkel B, Hoegner K, Clausen BE, Lewe-Schlosser P, Bodner J, Gattenloehner S, Seeger W, Lohmeyer J, Herold S. Alveolar epithelial cells orchestrate dendritic cell functions by release of granulocyte-ma-cophage colony stimulating factor in influenza virus pneumonia. J Clin Invest 122(10):3652-64, 2012.

4. Herold S, Shafiei Tabar T, Janßen H, Högner, K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmüller M, Lohmeyer J. Exudate macrophages attenuate epithelial injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183:1380-1390, 2011.

5. Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Seeger W, Lohmeyer J. Lung epithelial apoptosis in influenza virus pneumonia: The role of macrophage TNF-related apoptosis-inducing ligand. J Exp Med 205(13):3065-77, 2008.

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Session 7Florian Klein

“Broadly Neutralizing Antibodies for HIV-1 Immunotherapy”

Institute of Virology, University of CologneFürst-Pückler-Str. 5650935 Cologne, Germany

B I O S K E T C H

Florian Klein is professor and director of the Institute of Virology at the University of Cologne. His rese-arch focuses on the development of human B lymphocytes and antibodies, with a particular interest in the humoral immune response to HIV-1 and other viral pathogens. Together with his team, he employs new approaches for single B cell analyses and humanized mouse models. In addition, his team conducts early-phase clinical trials to translate basic laboratory findings into clinical applications. Florian Klein received his MD degree from Cologne University in 2005 following clinical training in inter-nal medicine. In 2009, he joined the Laboratory of Molecular Immunology at the Rockefeller University, where he became Instructor in Clinical Investigation in 2011, Chief Clinical Scholar in 2012, and Assistant Professor in 2013. In 2015, Dr. Klein took up a DFG-Heisenberg-Professorship at the University of Cologne and became professor in Virology in 2017.

A B S T R A C T

Broadly neutralizing antibodies (bNAbs) targeting HIV-1 can prevent infection in animal models and are under investigation for passive immunization in clinical trials. Moreover, bNAbs have been demons-trated to suppress viremia in HIV-1-infected individuals. While these results highlight the significant clinical potential of bNAbs, pre-existing and de novo HIV-1 resistance causes treatment failure and limits bNAb applications in humans. Strategies to overcome viral escape and to enhance the efficacy of bNAbs are therefore critical. We will discuss current approaches to successfully implement antibody-mediated therapy in HIV-1 infection.


1. Ehrhardt SA*, Zehner M*, Krähling V, Cohen-Dvashi H, Kreer C, Elad N, Gruell H, Ercanoglu MS, Schommers P, Gieselmann L, Eggeling R, Dahlke C, Wolf T, Pfeifer N, Addo MM, Diskin R, Becker S, Klein F. Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV. Nat Med (2019)

2. Mendoza P*, Gruell H*, Nogueira L, Pai JA, Butler AL, Millard K, Lehmann C, Suárez I, Oliveira TY, Lorenzi JCC, Cohen YZ, Wyen C, Kümmerle T, Karagounis T, Lu CL, Handl L, Unson-O‘Brien C, Patel R, Ruping C, Schlotz M, Witmer-Pack M, Shimeliovich I, Kremer G, Thomas E, Seaton KE, Horowitz J, West AP Jr, Bjorkman PJ, Tomaras GD, Gulick RM, Pfeifer N, Fätkenheuer G, Seaman MS, Klein F*, Caskey M*, Nussenzweig MC*. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature. (2018)

3. Caskey M.*, Schoofs T.*, Gruell H.*, Settler A., Karagounis T., Kreider E.F., Murrell B., Pfeifer N., No-gueira L., Oliveira T.Y., Learn G.H., Cohen Y.Z., Lehmann C., Gillor D., Shimeliovich I., Unson-O’Brien C., Weiland D., Robles A., Kümmerle T., Wyen C., Levin R., Witmer-Pack M., Eren K., Ignacio C., Kiss S., West A.P., Mouquet H., Zingman B.S., Gulick R.M., Keler T., Bjorkman P.J., Seaman M.S., Hahn B.H., Fätkenheuer G., Schlesinger S.J., Nussenzweig M.C.*, Klein F.*, Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat Med. (2017)

4. Klein, F.*, Diskin, R.*, Scheid, J.F., Gaebler, C., Mouquet, H., Georgiev, I.S., Pancera, M., Zhou, T., Incesu, R.B., Fu, B.Z., Gnanapragasam, P.N., Oliveira, T.Y., Seaman, M.S., Kwong, P.D., Bjorkman, P.J., and Nus-senzweig, M.C., Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell. (2013)

5. Klein, F., Halper-Stromberg, A., Horwitz, J.A., Gruell, H., Scheid, J.F., Bournazos, S., Mouquet, H., Spatz, L.A., Diskin, R., Abadir, A., Zang, T., Dorner, M., Billerbeck, E., Labitt, R.N., Gaebler, C., Marcovecchio, P.M., Incesu, R.B., Eisenreich, T.R., Bieniasz, P.D., Seaman, M.S., Bjorkman, P.J., Ravetch, J.V., Ploss, A., and Nussenzweig, M.C., HIV therapy by a combination of broadly neutralizing antibodies in humani-zed mice. Nature. (2012)

(*equal contribution)

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Session 7Melanie Greter

“Life and Fate of Brain Macrophages”

Institute of Experimental ImmunologyUniversity of Zurich, Zurich, Switzerland

B I O S K E T C H

Melanie and her team are interested in the development, regulation and function of mononuclear pha-gocytes in health and disease, with a specific focus on brain macrophages

Melanie Greter received her PhD at the University of Zurich from the Institute of Neuroimmunology in 2007. After her postdoctoral fellowship in Miriam Merad’s lab at the Mount-Sinai School of Medicine in New York, she moved back to Zurich to establish her own group in 2011. Since 2013, she is an SNSF (Swiss National Science Foundation) professor in the Institute of Experimental Immunology at the University of Zurich.

A B S T R A C T

Central nervous system (CNS) macrophages comprise parenchymal microglia and border-associated macrophages (BAMs) residing in the meninges, the choroid plexus and the perivascular spaces. With the exception of the more heterogeneous choroid plexus macrophages, they mostly emerge from early erythro-myeloid precursors in the extra-embryonic yolk sac. Whether these distinct brain macropha-ges share a developmental program or arise from individual predefined pathways is not clear. Here, we identified two phenotypically, transcriptionally and locally distinct brain macrophage populations throughout development, giving rise to microglia and BAMs. Two separate macrophage populations were already existent in the yolk sac prior to their seeding of the brain. The differentiation of microglia was dependent on the receptor for TGF-β during development whereas the genesis and maturation of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages represent independent entities in terms of ontogeny, gene expression profiles and requirement for TGF-β.


1. Yu X, Buttgereit A, Lelios I, Utz S, Cansever D, Becher B, Greter M. The cytokine TGF-β promotes the development and maintenance of alveolar macrophages. Immunity. 2017 Nov 21;47(5):903-912.e4

2. Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski RN, Gautier EL, Nishinakamura R, Becher B, Gre-ter M. Sall1 is a transcriptional regulator defining microglia fate and function. Nat Immunol. 2016 Dec;17(12):1397-1406

3. Mrdjen D, Pavlolvic A, Hartmann FJ, Schreiner B, Utz S, Leung BP, Lelios I, Heppner FL, Kipnis J, Merk-ler D, Greter M and Becher B. High-Dimensional Mapping of the Immune Atlas in the Central Nervous System During Health, Aging and Disease Immunity. 2018 Feb 20;48(2):380-395.e6

4. Greter M, Lelios I, Pelczar P, Hoeffel G, Price J, Leboeuf M, Kündig TM, Frei K, Ginhoux F, Merad M, Becher B. Stroma-derived IL-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity, 2012 Dec 14;37(6):1050-60

5. Ginhoux F, Greter M, Leboeuf M, Gouon-Evans V, Stanley RE, Samokvalov IM, Merad M. Fate map-ping studies reveal that adult microglia derive from primitive macrophages. Science, 2010 Nov 5;330(6005):841-5

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Session 8Frédéric Geissmann

“Genetic and developmental basis for macrophages functions”

Immunology Program, Sloan Kettering InstituteMemorial Sloan Kettering Cancer Center, New York, USA


1. Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J, Rauner M, Yadav VK, Crozet L, Bohm M, Loyher PL, Karsenty G, Waskow C Geissmann F. Developmental origin, functional main-tenance and genetic rescue of osteoclasts. Nature. 2019 Apr;568(7753):541-545. doi: 10.1038/s41586-019-1105-7. Epub 2019 Apr 10.

2. Mass E, Jacome-Galarza CE, Blank T, Lazarov T, Durham BH, Ozkaya N, Pastore A, Schwabenland M, Chung YR, Rosenblum MK, Prinz M, Abdel-Wahab O, Geissmann F. A somatic mutation in erythro-mye-loid progenitors causes neurodegenerative disease. (2017) Nature 549(7672):389-393. doi: 10.1038/nature23672. PMID: 28854169

3. Elvira Mass, Ivan Ballesteros, Matthias Farlik, Florian Halbritter, Patrick Gunther, Lucile Crozet, Christian E. Jacome-Galarza, Kristian Handler, Johanna Klughammer, Yasuhiro Kobayashi, Elisa Gomez-Perdiguero, Joachim L. Schultze, Marc Beyer, Christoph Bock, Frederic Geissmann. Speci-fication of tissue-resident macrophages during organogenesis (2016) Science. pii: aaf4238. PMID: 27492475 PMCID: PMC5066309

4. Stamatiades EG, Tremblay ME, Bohm M, Crozet L, Bisht K, Kao D, Coelho C, Fan X, Yewdell WT, David-son A, Heeger PS, Diebold S, Nimmerjahn S, Geissmann F. Immune Monitoring of Trans Endothelial Transport by Resident Kidney Macrophages (2016) Cell 166: 991-1003. doi: 10.1016/j.cell.2016.06.058. Epub 2016 Jul 28. PMID: 27477514 PMCID: PMC4983224

5. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Ja-cobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. (2012) Science. 336:86-90. PMID: 22442384.

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Session 8Thomas Gebhardt

“A new melanoma platform to study spontaneous immunity, cancer- immune equilibrium and immune control of metastatic disease”

Senior Medical Research Fellow (Sylvia & Charles Viertel Charitable Foun-dation) Department of Microbiology & Immunology, The University of Mel-bourne | Peter Doherty Institute for Infection and Immunity, Victoria, 3000 Melbourne, Australia

B I O S K E T C H

Thomas is a laboratory head in the Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, the University of Melbourne. His team studies basic and trans-lational aspects of immune responses in peripheral tissues. Their work pioneered the discovery and transcriptional and functional characterisation of tissue-resident memory T cells (TRM), a population of T cells now widely regarded as key mediators of protective immunity in barrier tissues. More recent-ly, they described the important function of TRM cells in controlling clinically occult melanoma. The overall goal of Thomas’ team is to understand the function of TRM cells in health and disease and to develop vaccines and immunotherapies that target TRM cells for improved clinical outcomes in infec-tion, inflammation and cancer.Thomas received training in clinical medicine and biomedical research at the Hanover Medical School, Germany, before joining the University of Melbourne in 2005. Over the years, he has been supported by a postdoctoral fellowship from the German Research Foundation, a RD Wright Career Development Award (NHMRC) and a CR Roper Fellowship (University of Melbourne), and currently holds the prestigi-ous Senior Medical Research Fellowship from the Sylvia & Charles Viertel Charitable Foundation.

A B S T R A C T

Tissue-resident memory T cells promote melanoma-immune equilibriumThe immune system can fight cancer by eliminating malignant cells or by preventing the outgrowth and spread of cancer cells that resist immune eradication. The nature and spatiotemporal dynamics of immune responses that efficiently control persisting cancer cells however have remained elusive. We have developed a transplantable melanoma model that approximates distinct disease stages seen in patients, including progressively growing tumours with metastatic spread, stably controlled tumours and long-term persistence of occult melanoma cells in absence of tumours. We have built key techno-logies around this model, including in vivo and ex vivo imaging techniques, as well as a gene editing platform that we are using to generate melanoma variants tailored to address defined experimental questions. Combined, these tools uniquely permit tracking, manipulation and imaging of melanoma and tumour-specific T cells, including a direct visualisation of localised T-cell-mediated tumour sup-pression. We are currently using this set-up to elucidate the contribution of tissue-resident memory T cells and other immune cells to the durable control of cutaneous melanoma and metastatic disease, and to uncover basic molecular pathways involved in efficient tumour suppression. Such fundamental knowledge that has the potential to guide the development and improvement of future cancer immuno-therapies.


1. Gebhardt T, Wakim LM, Eidsmo LA, Reading PC, Heath WR, Carbone FR. Non-lymphoid tissue-resi-dent memory T cells that provide enhanced local immunity in HSV infection. Nat Immunol 2009 (10:524–530). Citations: 545

2. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 2011 (477:216–219). Cita-tions: 287

3. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN, Heath WR, Carbone FR, Gebhardt T. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci USA 2012 (109:7037–7042). Citations: 273

4. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T. The development pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat Immunol 2013 (14:1294–1301). Citations: 399

5. Park SL, Buzzai A, Rautela J, Hor JL, Hochheiser K, Effern M, McBain N, Wagner T, Edwards J, McCon-ville R, Wilmott JS, Scolyer RA, Tüting T, Palendria U, Gyorki D, Mueller SN, Huntington ND, Bedoui S, Hölzel M, Mackay LK, Waithman J, Gebhardt T. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature 2019 (565:366-371). Citations: 14

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Session 8Michael Dustin

“Supramolecular attack particles: a new cytotoxic biomaterial”

Professor of Immunology and Wellcome Trust Principal Research FellowThe Kennedy Institute of RheumatologyUniversity of Oxford

B I O S K E T C H

Dr. Dustin is a basic scientist with a focus on understanding interactions between cells of the immune system. He joined the University of Oxford in 2013 after working for 13 years at NYU School of Medicine and 7 years at Washington University School of Medicine. Dr. Dustin’s work on basic mechanisms of immune cell function began when he was a graduate student with Timothy Springer at Harvard Medical School, where he described links between innate and adaptive immunity through regulation of adhesi-on molecules. His work at Washington University led to the first dynamic description of immunological synapse, work recognized by a Presidential Early Career Award in Science and Engineering. At NYUSOM, Dr. Dustin continued innovative studies of the immunological synapse, including discovery of synaptic ectosomes as a new messenger in the immune system, and has imaged the immunological synapse in vivo. At the Kennedy Institute of Rheumatology in Oxford he has undertaken a program to develop the-rapies for autoimmune diseases. He has published over 300 peer reviewed papers and review articles. He has also authored several patents, one of which led to the first “biologic” drug approved for treat-ment of psoriasis. NIH has recognized his work through a Merit Award, presentation of the Director’s lecture and funding of a Nanomedicine Development Center (2008-2012). Dr. Dustin currently holds a Wellcome Trust Principle Research Fellowship focusing on Translation of the Immunological Synapse, a European Research Council Advanced grant on synaptic ectosomes and a Human Frontiers Science Program grant on antibody formation.

A B S T R A C T

Supramolecular attack particles: a new cytotoxic biomaterialT cells communicate through direct cell-cell contact across gaps of only 13 nm (immunological synapse) or through secreted cytokines (1) or cytolytic proteins (2). I will present data from my lab on the role of CD2 expression in immunological synapse structure and on an intermediate mode of communication based on T cell export of vesicles and non-vesicular particles to antigen presenting cells across im-munological synapses. I will present data that CD2-CD58 interactions amplify TCR signals and the low CD2 expression has a similar impact to engaging PD1 on signaling parameters (https://www.biorxiv.org/content/ 10.1101/589440v1). Vesicles that are generated in the immunological synapse by budding from the plasma membrane into the extracellular space are referred to as synaptic ectosomes (SYNECT) (3-5). SYNECTs combine both antigen recognition and effector function and thus may maintain specificity even if they escape the initial synaptic interaction. In contrast, cytotoxic CD8+ T cells release non-lipid bilayer enveloped cytotoxic microparticles into the synaptic cleft (Balint, Fisher, Kessler. Harkiolaki and Dustin, in preparation). SMAPs are held together by multiple non-covalent protein-protein and pro-tein-carbohydrate interactions and are referred to as supramolecular attack particles (SMAPs).

SMAPs lack TCR, but appear to incorporate innate recognition molecules. I will describe the compositi-on, structure and function of SYNECTs and SMAPs and discuss potential applications.


1. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synap-se: a molecular machine controlling T cell activation. Science. 1999;285(5425):221-7. PubMed PMID: 10398592.

2. Somersalo K, Anikeeva N, Sims TN, Thomas VK, Strong RK, Spies T, Lebedeva T, Sykulev Y, Dustin ML. Cytotoxic T lymphocytes form an antigen-independent ring junction. J Clin Invest. 2004;113(1):49-57. PubMed PMID: 14702108.

3. Choudhuri K, Llodra J, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL, Dustin ML. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature. 2014;507(7490):118-23. Epub 2014/02/04. doi: 10.1038/nature12951. PubMed PMID: 24487619

4. Papa I, Saliba D, Ponzoni M, Bustamante S, Canete PF, Gonzalez-Figueroa P, McNamara HA, Valvo S, Grimbaldeston M, Sweet RA, Vohra H, Cockburn IA, Meyer-Hermann M, Dustin ML, Doglioni C, Vinuesa CG. TFH-derived dopamine accelerates productive synapses in germinal centres. Nature. 2017;547(7663):318-23. doi: 10.1038/nature23013. PubMed PMID: 28700579

5. Saliba DG, Cespedes-Donoso PF, Balint S, Compeer EB, Korobchevskaya K, Valvo S, Mayya V, Kvalvaag A, Peng Y, Dong T, Tognoli ML, O‘Neill E, Bonham S, Fischer R, Kessler BM, Dustin ML. Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand from helper T-cells. eLife. 2019;8:600551. Epub 2019/08/31. doi: 10.7554/eLife.47528. PubMed PMID: 31469364.

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NotesNotes

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1 Adina Apartment Hotel Berlin Mitte

Platz vor dem Neuen Tor 6 10115 Berlin

120 / N20

Berlin -Hauptbahnhof

M5 / M8 / M10120/123/142/147/245 / M41/ M85/N20/ N40/TXL

TXL/142142/ 147/ 245/ N40/TXL

142

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3/5/ 7/9

M5 / M8 / M10

FriedrichstraßeOranienburger Tor

147

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1/2/3/5/7/9/25/26

M1 / 12

147/ 245

Marschallbrücke

245

147/ 245

Schumannstr.

Sauerbruchweg

Virchow

weg

Charité-platz

Bonhoefferw

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Hirsch

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Rahel-W

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Hufe- la

nd

- we

g

Lu

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str.

Rahel-Hi rsch

-Weg

Hufelandw

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Robert-Koch-Platz

HannoverscheStr.

Hessische Str.

Charitéstr.

Str.

Hannoversche

Invalidenstr.

Unter

baum

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str.

Margarete-Steffin-Str.

Alexander-ufer

Kapelle-UferKarl-platz Reinhardtstr.

Philippst

r.

1

2 Hörsaalruine

Visiting address

Virchowweg 16

3 Wilhelm-Waldeyer Haus

Philippstraße 12, 10115 BerlinThe gate entrance on the right next to Luisenstr. 57 using the path follow the path into the park area and keep left. After approx. 100 m you will reach the main entrance to Wilhelm-Waldeyer Haus (Center for Anatomy).

https://future-of-immunology-berlin.charite.de/en/ e-mail: [email protected]

Symposium – Future of Immunology @ BerlinCharité – Universitätsmedizin Berlin | Campus Charité Mitte

Hessische Str.

Adina Apartment Hotel Berlin Mitte

2

Hörsaalruine

Wilhelm-WaldeyerHaus

3

Map

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