Thursday 6 – Friday 7 June 2013

Amphi 1, Institut Le Bel

Université de Strasbourg

“Frontiers in Innate Immunity”

France-Japan Joint Forum

“Frontiers in Innate Immunity”

organized by JSPS, Université de Strasbourg, CNRS, MUFJ

With the support of: Région Alsace

Strasbourg City Consulat Général du Japon à Strasbourg

Organizers: Jean-Marc Reichhart, Chihiro Sasakawa, Marie-Claire Lett, Yoichi Nakatani

Secretariat: Satoko Tada, Valérie Wolf, Hitomi Ogawa

Video of the forum is available on Canal C2: http://www.canalc2.tv/

6 June 2013 (Thursday)

9:00 - 9:45 Opening session - Prof. Catherine Florentz (Vice-President, University of Strasbourg)

*representing Prof. Alain Beretz, President of UDS

- Mr. Susumu Hasegawa (Consul General of Japan in Strasbourg)

- Prof. Patrick Netter (Former-Director of the INSB, CNRS)

- Mr. Roland Ries (Mayor of Strasbourg)

- Mr. Jacques Bigot (President, Communauté urbaine de Strasbourg)

- Mr. Philippe Richert (President, Conseil Régional d’Alsace)

- Mr. Hisashi Kato (Director, International Program Department, JSPS)

Session 1 Chairperson: Prof. Jean-Marc Reichhart 9 :45 - 10 :30 (Talk 1)

Prof. Jules Hoffmann, Institut de Biologie Moléculaire et Cellulaire, UDS “ Innate Immunity : From Flies to Humans”

10:30 - 11:15 (Talk 2)

Prof. Chihiro Sasakawa, Nippon Institute for Biological Science, Medical Mycology Research Center, Chiba University “Bacteria and gut interplay: Circumvention of intestinal mucosal barriers by Shigella”

11:15 - 12:00 (Talk 3)

Prof. Jean-François Bach, French Academy of Sciences, Paris “New concepts on the etiology of autoimmune and allergic diseases: The role of infections and of the intestinal microbiome”

12:15 Photo Session

12:30 Lunch Buffet

Session 2 Chairperson: Prof. Chihiro Sasakawa 14:00 - 14:45 (Talk 4)

Prof. Hiroshi Kiyono, Institute of Medical Science, The University of Tokyo “ Mucosal Connection for Immunity, Tolerance and Commensal Microbiota”

14:45 - 15:30 (Talk 5)

Prof. Kensuke Miyake, Institute of Medical Science, The University of Tokyo “TLR logistics by Unc93B1 as a mechanism regulating autoimmunity”

15:30 - 16:00 Coffee Break

16:00 - 16:45 (Talk 6)

16:45 - 17:30 (Talk 7)

Prof. Laurence Zitvogel, Center for Clinical Investigation, Villejuif “The Anti-cancer Immune Response – Indispensable for Therapeutic Success?”

Prof. Osamu Takeuchi, Institute for Virus Research, Kyoto University “Posttranscriptional control of inflammation by an RNase, Regnase-1”

Program

7 June 2013 (Friday) Session 3 Chairperson: Prof. Jean-Luc Imler 9:00 - 9:45 (Talk 8)

Prof. Eric Vivier, Centre d’Immunologie de Marseille-Luminy “Cellules Natural Killer, Innate Lymphoid Cells et Immunité Innée”

9:45 - 10:30 (Talk 9)

Prof. Tsuneyasu Kaisho, Immunology Frontier Research Center, Osaka University “ In vivo roles of dendritic cells expressing a chemokine receptor, XCR1”

10:30 - 11:00 Coffee Break

11:00 - 11:45 (Talk 10)

Prof. Sebastian Amigorena, Unit 653 Inserm Immunity of Cancer, Insitute Curie, Paris “ ER, phagosomes and cross presentation in dendritic cells”

11:45 - 12:15 Ms. Satoko Tada, JSPS Strasbourg Office “JSPS International Programs”

12: 15 - 12:30 Closing remarks - Prof. Reichhart, Prof. Sasakawa, Prof. Nakatani

12:30 - 14:00 Lunch Buffet

Session 4 Chairperson: Prof. Serge Potier 14:00 - 16:00 Round Table with students and Prof. Jules Hoffmann

Prof. Marie-Claire Lett, Université de Strasbourg, Maison Universitaire France - Japon “Experiences in Japan under the JSPS Fellowship Program”

16:00 - 16:45 Coffee Break

19:00 Reception hosted by the Strasbourg City

Forum Abstracts and CVs (Speakers)

Session 1

Innate Immunity : From Flies to Humans

Jules Hoffmann Institut de Biologie Moléculaire et Cellulaire,

UPR 9022 du CNRS, UPR 9022 du CNRS

When challenged with fungi or bacteria, flies rapidly transcribe several hundreds of genes, primarily but not exclusively, in their fat body and blood cells. Among these are some 25 genes which encode small-sized cationic antimicrobial peptides with various activity spectra. These peptides are secreted into the blood where their high concentrations oppose invading microorganisms. Genetic analysis has identified two signaling pathways which control the expression of these peptides : the Toll pathway, which primarily controls the response to fungi and Gram-positive bacteria, and the IMD pathway which is efficient in fighting Gram-negative bacterial infections. The Toll pathway is activated by binding of the transmembrane receptor Toll to a cleaved form of the cytokine Spaetzle : this cleavage is dependent on complex proteolytic cascades in the blood which are triggered by interaction of fungal glucans or Lysine-type peptidoglycans with dedicated circulating recognition proteins of the Glucan Binding Protein (GNBP) and the Peptidoglycan Recognition Protein (PGRP) families respectively. The IMD pathway is activated by the direct interaction of Diaminopimelic acide-type peptidoglycans with a transmembrane receptor of the PGRP family.

The studies on the recognition proteins of microbial invaders, on the signaling cascades triggered by this recognition and the subsequent control of expression of genes encoding effector proteins, have led to the discovery of an unexpected commonality between the fly and mammalian innate immune responses. In particular, the Toll and PGRP transmembrane receptors – initially discovered in flies - are conserved in the vertebrate phylum. Studies performed in many laboratories over the last decade, both on basic and clinical aspects, point to a role of the mammalian Toll-like receptors in a variety of important conditions, such as inflammation, defense against infection, autoimmunity, and are also relevant for vaccination and immunotherapy. PGRPs on the other hand appear to play a central role in the control of the gut microbiota and in epithelial antimicrobial defenses.

Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. Cell. 1996; 86 :973. Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA. Science. 1999; 284: 1313. Hoffmann JA. Nature. 2003; 426: 33. Ferrandon D, Imler JL, Hetru C, Hoffmann JA. Nat Rev Immunol. 2007; 7: 862. Lemaitre B, Hoffmann J. Annu Rev Immunol. 2007; 25: 697. Kawai T, Akira S. Immunity. 2011; 34: 637. Royet J, Gupta D, Dziarski R. Nat Rev Immunol. 2011; 11: 837. Kemp C et al J. Immunol. 2013; 650-658.

Jules A. Hoffmann Born in Echternach (Luxembourg) Married, two children (1970, 1974). French citizen.

Studies General Education in Luxembourg (up to 1960) University studies in Biology and Chemistry at the University of Strasbourg (1961-1965) Doctoral thesis (Ph.D) in Biology, University of Strasbourg (1969)

Functions Emeritus Distinguished Class Research Director at CNRS and Group Leader, Past President of the French National Academy of Sciences (2007—2008), Chair of Integrative Biology, Professor at University of Strasbourg Institute for Advanced Study. Previous : Director of the CNRS Research Unit 9022 "Immune Response and Development in Insects" (1978-2005) Director of the Institute of Molecular and Cellular Biology, CNRS, Strasbourg (1993-2005) Research Director, CNRS, 1974-2009, Research Associate, CNRS, 1969-1973. Research Assistant, CNRS, 1964-1968. Research Training Assistant, CNRS, 1963. Laboratory Assistant at the Faculty of Sciences of the University of Strasbourg, 1962. Post-doctoral training Institut für Physiologische Chemie, Philipps Universität, Marburg an der Lahn. Professor P. Karlson, 1973-1974. Member of Academies Elected to the Académie française, 2012. National Academy of Sciences (NAS), 2008. Russian Academy of Sciences, 2006. American Academy of Arts and Sciences, 2003. Member of EMBO (European Molecular Biology Organization), 1995. Academia Europaea, 1993. French National Academy of Sciences, 1992. German Academy of Sciences Leopoldina, 1987. Distinctions honoris causa Member, Académie de Médecine, Paris, 2012. Nobel Prize in Physiology or Medicine, 2011. Médaille d’Or CNRS, 2011. Canada Gairdner Award, 2011. The Shaw Prize, Life Science and Medicine, 2011. Keio Prize for Medical Research, 2010. Lewis Rosenstiel Award for Innate Immunity, 2010. Balzan Prize for Innate Immunity, 2007. Dr honoris causa med., Technische Universität Munich, 2006. Robert Koch Prize for Immunology, 2004.

Grand Prix de la Fondation pour la Recherche Médicale, 2004. William B. Cooley Award for Basic and Tumor Immunology, Cancer Research Institute, 2003. Prix Lacassagne, Collège de France, 1996. Grand Prix Joannidès de l'Académie des Sciences, 1992. Alexander von Humboldt Price, 1984. Pergamon Price, 1980. Sandoz-Wander Price, 1978.

Session 1

Bacteria and gut interplay: Circumvention of intestinal mucosal barriers by Shigella

Chihiro Sasakawa

Nippon Institute of Biological Science, Tokyo Medical Mycology Research Center, Chiba University

Institute of Medical Science, University of Tokyo

Bacteria–gut mucosa interplay and the mucosal immune responses are the most critical issues in determining the fate of bacterial colonization and the success of host defense. Shigella are highly adapted human pathogens and the causative agent of bacillary dysentery. We have extensively studied Shigella as a model pathogen. Shigella are capable of killing macrophages, invading and replicating within the epithelium, and spreading cell-to-cell, all of which are required for promoting bacterial colonization of the intestinal mucosa and eventually the development of severe inflammatory colitis, commonly referred to as bacillary dysentery. Host innate immune systems can sense bacterial infections of the gut mucosa as PAMPs and DMPAs using various pathogen recognition receptors, such as NOD-like receptors, thus leading to activation of various host defense systems. However, Shigella deploy countermeasures against the host defense by secreting a variety of virulence-associated proteins, known as effectors, via the type III secretion system (T3SS) during infection. Some of these bacterial effectors are delivered into the surrounding bacterial space as well as into the host cell cytoplasm and nucleus, where they mimic and usurp various host cellular functions and signaling pathways for promoting infection. Some other effectors, which are mostly delivered by bacteria replicating within host cells, play a role in circumventing the intrinsic mucosal defense barriers and modulating innate immune responses to bacterial infection.

In this forum, I will present several of our recent findings related to the Shigella activities to circumvent the gut epithelial barriers and modulate host innate immune responses. These activities are predominately executed by a subset of effectors that are secreted via the bacterial T3SS. Kobayashi T, et al. Cell Host Microbe 2013 Ashida H, et al. PLoS Pathog 2013 Nishida et al. J Mol Biol 2013 Fukumatsu M, et al. Cell Host Microbe 2012 Sanada T, et al. Nature 2012 Ashida et al. Nat Chem Biol 2011

Chihiro Sasakawa Professor Emeritus, Institute of Medical Science, University of Tokyo Managing Director, Nippon Institute of Biological Science Director, Medical Mycology Research Center, Chiba University Address: 9-2221-1, Ome-shinmachi, Ome, Tokyo Japan Phone: +81 04 28 33 10 67 E-mail: sasakawa@ims.u-tokyo.ac.jp

Chihiro Sasakawa received his PhD from The University of Tokyo in 1978. From 1980 to 1983, he undertook postdoctoral studies in the Department of Microbiology and Immunology at Washington University. Upon returning to Tokyo, he initiated studies on bacterial pathogenesis at the Institute of Medical Science, The University of Tokyo. In 1995 he became a professor and served as the Head of Department of Microbiology and Immunology from 1999 to 2005. He was named a Professor Emeritus of The University of Tokyo in 2012. He continuously presents his research and participates in academia as a member of the Science Council of Japan since 2011, the President of Federation of Microbiological Societies of Japan since 2012, and the Director of Medical Mycology Research Center at the Chiba University since 2013.

Over the past 30 years, his group has made significant contributions to the broader field of bacterial pathogenesis and host defense using several pathogens including Shigella, Helicobacter pylori, enterohaemorrhagic E. coli, and enteropathogenic E. coli. His research has been published in more than 200 articles in peer-reviewed journals including Nature, Cell, and Science. He is currently a member of the editorial or advisory boards of Cell Host & Microbe, Nature Reviews Microbiology, Trends in Microbiology, Current Opinion of Microbiology, and several other international journals.

Session 1

Jean-François Bach Académie des sciences

Jean-François Bach est Docteur en médecine et Docteur es sciences de l’Université de Paris. Il a mené une triple activité de recherche, d’enseignement et de soins comme Professeur des universités et praticien hospitalier à l’Hôpital Necker. Il est depuis 2006 Secrétaire Perpétuel de l’Académie des sciences où il avait été élu en 1985. Il est également membre de l’Académie nationale de médecine, de l’Académie nationale de pharmacie et de l’Académie of medical sciences au Royaume-Uni. Ces travaux concernent l’immunologie et plus particulièrement les bases fondamentales de l’auto-immunologie, l’immunothérapie dans les maladies auto-immunes et en transplantation d’organes et le rôle des infections dans le déclenchement des maladies auto-immunes et allergie.

Session 2

Mucosal Connection for Immunity, Tolerance and Commensal Microbiota

Hiroshi Kiyono

Division of Mucosal Immunology, Department of Microbiology and Immunology,

International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo

The intestinal tract is covered by a single layer of epithelium which continuously exposed to infinite beneficial and harmful antigens including commensal and pathogenic microbe, and foods in handling its day-to-day duties. The digestive tract is thus equipped with the mucosal immune system (MIS) offering the first line of surveillance and defense forces against invasion of undesired antigens and pathogens. At same time, the MIS also expose to an enormous number and volume of innocuous and/or instructive antigens (e.g., commensal microorganisms) which need to be appropriately ‘ignored’. Mounting an immunologically harmonized response therefore represents a key decision-making process of active and/or quiescent immune responses by the MIS. To this end, the MIS has been shown to be enriched with the variety of innate and acquired immunity-associated cells. Our studies have provided a new evidence for the intra-tissue habitation of commensal flora in the organized lymphoid structure associated with gut mucosa (e.g., Peyer’s patch:PP) which involves in the development of IgA immune system and creation of homeostatic condition (or physiological inflammation). Further, recent evidences have suggested that intestinal innate lymphoid cells (ILC) play a critical role in the containment of Alcaligenes in PP. Intestinal epithelial cells possess unique α(1,2)- fucose- moiety and these cells are thus refereed as fucosylated ECs (F-ECs) which are contributing in the formation of co-habitation platform for commensal bacteria. F-ECs are induced and maintained by commensal bacteria. Furthermore, these epithelial fucosylation is induced and regulated by mucosal innate immunity-associated cells. Our most recent study has demonstrated that mucosal mast cells expressing P2X7 purinoceptors play critical role in the induction and regulation of intestinal inflammation via extracellular ATP. Thus, our data provide a new perspective of the mucosal connection links with mucosal innate immunity associated cells, epithelial cells and intestinal microbiota for the gut mutualisum (or physiological inflammation) and the disruption of the trialogue mucosal connection system may lead to the development of pathological condition including undesired inflammation and food allergy.

Hiroshi Kiyono Dean and Professor Division of Mucosal Immunology, Department of Microbiology and Immunology, International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo

Dr. Kiyono obtained his dental degree (D.D.S.) from Nihon University, and Ph. D. from the University of Alabama at Birmingham (UAB). His background as a dentist combined with extensive research experience in the field of Mucosal Immunology at UAB, Max-Planck Institute, Osaka University and now, the University of Tokyo make him exceptionally well qualified to discuss the current and future direction of mucosal immunology and mucosal vaccine. To reflect his scientific contribution, he has been listed in ISI Highly Cited Researchers’ List since 2005. He is the past President of Society for Mucosal Immunology. He received of several prestigious awards including NIH New Investigator Research Award, NIH Research Career Development Award, The Japanese Society for Vaccinology Takahashi Award, and Hideyo Noguchi Memorial Medical Science Award. He has a total of 422 publications in peer review journals and edited a total of 20 books. He is currently Dean, the Institute of Medical Science, the University of Tokyo.

Session 2

TLR logistics by Unc93B1 as a mechanism regulating autoimmunity

Kensuke Miyake

Div. Innate Immunity, Inst Med. Sci., Univ. Tokyo, Japan

The Toll family of receptors has critical roles in microbial recognition and activation of defense responses. Cell surface Toll-like receptors (TLRs) including TLR4/MD-2, TLR1/TLR2, TLR2/TLR6, or TLR5 recognize microbial membrane lipids or flagellin, whereas TLR3, 7, 8, and 9 reside in intracellular organelle and sense nucleic acids. Recent progresses have revealed that self-pathogen discrimination by TLRs is error prone and TLRs have been implicated in a variety of autoimmune diseases. Although the ligand specificity and downstream signaling pathways of each TLR have been extensively studied, much less is known as to how innate immune responses to self-products are controlled. Nucleic acid-sensing TLRs, TLR7, 8 and 9, have a risk of responding to self-derived nucleic acids. To prevent autoimmune responses, these TLRs are thought to be controlled by restricting nucleic acid sensing in endolysosomes, not the cell surface. Extracellular self-nucleic acids are instantly degraded and do not get to endolysosomes, whereas microbial nucleic acids are protected by microbial membranes and get to the endolysosomes. To limit nucleic acid sensing in endolysosomes, two mechanisms are proposed, nucleic acid sensing by truncated forms and trafficking of nucleic acid-sensing TLRs from ER to endolysosomes. The subcellular distribution of TLR7 and 9 are dependent on a multiple transmembrane protein Unc93B1. It is important to understand how Unc93B1-dependent TLR trafficking and TLR proteolytic cleavage regulate innate immune response to self-nucleic acids.

Kensuke Miyake Professor Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo Address: 4-6-1, Shirokanedai, Minatoku, 108-8639 Tokyo, Japan Phone: +81 03 54 49 52 94 Fax: +81 03 54 49 54 10 E-mail: kmiyake@ims.u-tokyo.ac.jp

Education: 1978-1984 Okayama University Medical School 1984-1988 Osaka University Medical School, Ph. D. awarded 3/88 Research Appointment: 1988-1990 Research associate, Oklahoma Medical Research Foundation, USA 1990-1993 Assistant professor, Saga Medical School 1993-2001 Associate professor, Saga Medical School 2001-current Professor, The Institute of Medical Science, The University of Tokyo Award: 1999 The 2nd JSI (the Japanese Society for Immunology) award 2000 The 37th Erwin von Bälz Award 2001 The 45th Hideyo Noguchi Memorial Award

Session 2

The Anti-cancer Immune Response – Indispensable For Therapeutic Success?

Laurence Zitvogel

INSERM, U1015 CIC BT507

Institut Gustave Roussy Faculté Paris Sud-Université Paris 11

Although the impact of tumor immunology on the clinical managements of most cancers is still negligible, there is increasing evidence that anti-cancer immune responses may contribute to the control of cancer after conventional chemotherapy. Thus, radiotherapy and some chemotherapeutic agents, in particular anthracyclines, oxaliplatine and X Rays can induce anticancer protective CD4+ and CD8+ T cell-based immune responses (Obeid et al. Nat. Med 2007, Apetoh et al. Nat Med 2007) that result either in immunogenic cancer cell death. Other regimen of chemotherapy also result in tumor sensitization to effector attack, in immunostimulatory “side effects” or in suppression of regulatory cells. This anti-cancer immune response then helps to eliminate residual cancer cells (that failed to be killed by chemotherapy) or maintains micrometastases in check, keeping them in a stage of dormancy.

In collaboration with MJ Smyth at the Peter Mac Callum Cancer Center, we delineated the molecular mechanisms underlying the recognition of dying tumor cells by dendritic cells (DC) and found four major checkpoints that dictate the immunogenicity of cell death. First, optimal phagocytosis of chemotherapy or radiotherapy-treated tumor cells by DC requires the translocation of ER-resident calreticulin (CRT) and disulfide isomerase ERp57 to the plasma membrane of dying tumor cells (Obeid et al. Nat Med 2007, Panaretakis et al. CDD 2008, Panaretakis et al. EMBO J 2009). Second, the chromatin-binding high mobility group box 1 protein (HMGB1) must be released by dying tumor cells and bind to its receptor toll-like receptor 4 (TLR4) on DC to facilitate antigen processing of the phagocytic cargo (Apetoh et al Nat Med 2007). Third, ATP has to be emitted by dying cells to engage P2RX7 on DC, triggering the activation of a cascade (Nlrp3 inflammasome>ASC>casp-1 cleavage>IL-1β maturation and secretion) leading to IL-1β-dependent Tc1 polarization of antigen-specific T cell responses. It is important to stress that the antitumor effects of anthracyclines, oxaliplatine and X Rays are abrogated in mice devoid of T cells, of a IFNγ/IFNγR functional pathway, of an IL-1β/IL-1R1 intact signaling while IL-12Rβ, perforine/TRAIL are dispensable for the tumoricidal effects of these compounds (Ghiringhelli et al. Nat Med. 2009). Fourth, the contexture of the tumor post-chemotherapy revealed that a precise T cell orchestration is required for the immune effectors to reject the tumor burden. Hence, IL-1β-dependent γδT17 cells precede the Tc1 CTL infiltrate and are indispensable for the efficacy of chemotherapy (Ma et al. JEM 2011, Matarollo, Cancer Res 2011). The IL-17/IL-17Ra pathway is mandatory for the immunogenicity of cell death and the success of chemotherapy. Overall, these molecular requirements dictating the efficacy of chemotherapy may promote the investigators to modify the routine management of cancer patient. Immunogenetics will help defining the immunological defects inherent to each individual patients prior to therapy urging for a distinct compensatory treatment while mapping the defects in the CRT exposure pathway may allow to predict tumor intrinsic defects that could be counteracted by defined therapies. Integrating immunological predictors in the current prognosis signatures may lead to personalization of anticancer clinical management. Based on these premises, we will discuss how it may be possible to ameliorate conventional therapies by stimulating the anti-cancer immune response. Moreover, we will discuss the rationale of clinical trials to evaluate and eventually increase the contribution of anti-tumor immune responses to the therapeutic management of neoplasia.

Selected publications (among more than 170), in Journals with an impact factor > 15:

Nicolas F. Delahaye, Sylvie Rusakiewicz, Isabelle Martins, Cédric Ménard, Stéphan Roux, Luc Lyonnet, Pascale Paul, Caroline Flament, Nathalie Chaput, Michaela Semeraro, Véronique Minard-Colin, Vichnou Poirier-Colame, Véronique Baud, Hélène Authier, Saadia Kerdine-Römer, Marc Pallardy, Dominique Valteau-Couanet, Pascal Rihet, Jean-Yves Blay, Nicolas Isambert, Jean-François Emile, Eric Vivier, Axel Le Cesne, Guido Kroemer, and Laurence Zitvogel.

Alternatively spliced NKp30 isoforms influence the prognosis of gastrointestinal stromal tumors.

Nat Med 2011, May 2. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. Ma Y, Aymeric L, Locher C, Mattarollo SR, Delahaye NF, Pereira P, Boucontet L, Apetoh L, Ghiringhelli F, Casares N, Lasarte JJ, Matsuzaki G, Ikuta K, Ryffel B, Benlagha K, Tesnière A, Ibrahim N, Déchanet-Merville J, Chaput N, Smyth MJ, Kroemer G, Zitvogel L. J Exp Med. 2011 Mar 14;208(3):491-503. Immune parameters affecting the efficacy of chemotherapeutic regimens. Zitvogel L, Kepp O, Kroemer G. Nat Rev Clin Oncol. 2011 Mar;8(3):151-60. Targeting dendritic cell metabolism in cancer. Zitvogel L, Kroemer G. Nat Med. 2010 Aug;16(8):858-9. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L. Semin Immunol. 2010 Jun;22(3):113-24. Epub 2010 Apr 18. Decoding cell death signals in inflammation and immunity. Zitvogel L, Kepp O, Kroemer G. Cell. 2010 Mar 19;140(6):798-804. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rébé C, Ghiringhelli F. J Clin Invest. 2010 Feb 1;120(2):457-71. The IKK complex contributes to the induction of autophagy. Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I, Kepp O, Tasdemir E, Galluzzi L, Shen S, Tailler M, Delahaye N, Tesniere A, De Stefano D, Younes AB, Harper F, Pierron G, Lavandero S, Zitvogel L, Israel A, Baud V, Kroemer G. EMBO J. 2010 Feb 3;29(3):619-31. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini JL, Schlemmer F, Tasdemir E, Uhl M, Génin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, André F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L. Nat Med. 2009 Oct;15(10):1170-8. Anticancer immunochemotherapy using adjuvants with direct cytotoxic effects. Zitvogel L, Kroemer G. J Clin Invest. 2009 Aug;119(8):2127-30. doi: 10.1172/JCI39991. Epub 2009 Jul 20.

Green DR, Ferguson T, Zitvogel L, Kroemer G. Nat Rev Immunol. 2009 May;9(5):353-63. Immunogenic and tolerogenic cell death.

CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. Roux S, Apetoh L, Chalmin F, Ladoire S, Mignot G, Puig PE, Lauvau G,

Zitvogel L, Martin F, Chauffert B, Yagita H, Solary E, Ghiringhelli F. J Clin Invest. 2008 Nov;118(11):3751-61.

Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. J Clin Invest. 2008 Jun;118(6):1991-2001. Review.

The anticancer immune response: indispensable for therapeutic success?

Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L. Nat Immunol. 2008 May;9(5):486-94. Review.

Natural killer cell-directed therapies: moving from unexpected results to successful strategies.

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G.Nat Rev Immunol. 2008 Jan;8(1):59-73. Review. Immunological aspects of cancer chemotherapy.

Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, André F, Delaloge S, Tursz T, Kroemer G, Zitvogel L.

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

Nat Med. 2007 Sep;13(9):1050-9.

Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Métivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G.

Calreticulin exposure dictates the immunogenicity of cancer cell death.

Nat Med. 2007 Jan;13(1):54-61. Cancer despite immunosurveillance: immunoselection and immunosubversion.

Zitvogel L, Tesniere A, Kroemer G. Nat Rev Immunol. 2006 Oct;6(10):715-27. Epub 2006 Sep 15. Review.

A novel dendritic cell subset involved in tumor immunosurveillance.

Taieb J, Chaput N, Ménard C, Apetoh L, Ullrich E, Bonmort M, Péquignot M, Casares N, Terme M, Flament C, Opolon P, Lecluse Y, Métivier D, Tomasello E, Vivier E, Ghiringhelli F, Martin F, Klatzmann D, Poynard T, Tursz T, Raposo G, Yagita H, Ryffel B, Kroemer G, Zitvogel L. Nat Med. 2006 Feb;12(2):214-9.

In vivo veritas.

Zitvogel L, Tursz T. Nat Biotechnol. 2005 Nov;23(11):1372-4.

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Borg C, Terme M, Taïeb J, Ménard C, Flament C, Robert C, Maruyama K, Wakasugi H, Angevin E, Thielemans K, Le Cesne A, Chung-Scott V, Lazar V, Tchou I, Crépineau F, Lemoine F, Bernard J, Fletcher JA, Turhan A, Blay JY, Spatz A, Emile JF, Heinrich MC, Mécheri S, Tursz T, Zitvogel L. J Clin Invest. 2004 Aug;114(3):379-88.

Exosomes: composition, biogenesis and function.

Théry C, Zitvogel L, Amigorena S. Nat Rev Immunol. 2002 Aug;2(8):569-79.

Malignant effusions and immunogenic tumour-derived exosomes.

Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E, Zitvogel L. Lancet. 2002 Jul 27;360(9329):295-305.

Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.

Wolfers J, Lozier A, Raposo G, Regnault A, Théry C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L. Nat Med. 2001 Mar;7(3):297-303.

Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo.

Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L. Nat Med. 1999 Apr;5(4):405-11.

Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Nat Med. 1998 May;4(5):594-600.

Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes.

Mayordomo JI, Zorina T, Storkus WJ, Zitvogel L, Celluzzi C, Falo LD, Melief CJ, Ildstad ST, Kast WM, Deleo AB, et al. Nat Med. 1995 Dec;1(12):1297-302.

Dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity.

Laurence Zitvogel INSERM, U1015 Institut Gustave Roussy Address: 114 rue Edouard Vaillant, F-94805 Villejuif, France Phone: +33 01 42 11 50 41 Fax: +33 01 42 11 60 94 E-mail: zitvogel@igr.fr

Pr L. Zitvogel, MD (clinical oncology), PhD (tumor immunology), PU-PH Faculty Paris Sud, University Paris XI (Clinical Biology), graduated in Medical Oncology from the School of Medicine of the University of Paris in 1992. She started her scientific career when she was at the University of Pittsburgh in the USA in Michael Lotze’s laboratory. She became Research Director at Institut National de la Santé et Recherche Médicale U1015, in a laboratory located at Institut Gustave Roussy, a large cancer Center in Villejuif/France and the Head of the Center for Clinical Investigations CICBT 507 for vaccine developments at Villejuif. She has been actively contributing to the field of cancer immunology and immunotherapy, and she brought together basic and translational research, including the design of cancer therapies through combined animal studies and Phase I patient trials. Her expertise is mainly dendritic cell and innate effector biology and relevance during tumour development as well as exosome-based vaccine designs. She pioneered the concept of immunogenic cell death and showed that chemotherapy, radiotherapy and inhibitors of tyrosine kinase mediate their tumoricidal activity, at least partly through the immune system. Education

. Appointments/Affiliations Dates Title Organization City, Country 2005- Director in Biotherapies

Curie/IGR Center for Clinical Investigation

Villejuif/Paris, France

2003- present Full Professor University Paris 11, Medical Faculty

Villejuif, France

2002- present Director INSERM Research Unit Villejuif, France 2000-2004 Program Coordinator European Community Brussels, Belgium 1995-2003 Associate Professor University Paris 11 Villejuif, France 1992-1995 Assistant Professor University Paris 11 Villejuif, France 1992-present Chief Physician Institut Gustave Roussy,

Breast Cancer Department Villejuif, France

1992-1995 Junior Associate in Immunotherapy

Pittsburgh Cancer Institute Pittsburgh,, PA, USA

1987-1992 Clinical Internship University Hospitals in Paris

Paris, France

Date Degree nstitution Subject 1998 Habilitation University Paris 11, Medical Faculty, France Immunology 1995 Ph.D. St. Louis Hospital, Paris 7, France Immunology 1992 Board Certificate Institut Gustave Roussy, Villejuif, France Clinical Oncology 1987 M.D Medical School Pitié Salpétrière, Paris 6 Medicine

Awards Honors/Awards Date Name 2008

Description Chevalier Order Legion Honneur French Ministery Research, FR

2007 Gallet Breton Price Academy of Sciences, France 2005 Charles Oberling Price Academy of Medicine, France 2000 Gustave Roussy Price Academy of Sciences, France 1999 Price of the Chancelor Universities of Paris, France 1996 Research Price League against Cancer, Comité Haute Loire, France 1995 Merit Award Society for Biological Therapy, Nappa Valley, USA 1994 Presidential Award American Society for Clinical Oncology, USA 1992 Fellowship Bleustein Blanchet Foundation for Scientific and Medical Vocation 1992 Gold Medal, Internal Medicine Institut Gustave Roussy, Villejuif, France

Session 2 Posttranscriptional control of inflammation by an RNase,

Regnase-1

Osamu Takeuchi Institute for Virus Research,

Kyoto University, Kyoto

Inflammation is initially evoked by the innate immune system in response to microbial infection and other cellular stresses. Proinflammatory cytokines produced by innate immune cells upon sensing of pathogens by Toll-like receptors (TLRs) are the mediators important for inflammation. The cytokine levels in innate immune cells are tightly controlled to prevent the development of septic shock and autoimmune diseases.

The expression of genes involved in inflammation is controlled both transcriptionally and post-transcriptioally. Cytokine mRNAs tend to be degraded rapidly by a set of RNA binding proteins.

Tristetraprolin is known to bind with TNF mRNA through AU rich elements in its 3’ untranslated region (UTR). On the other hand, Regnase-1 (also known as Zc3h12a or MCPIP1) is critical for suppressing mRNA for IL-6 and IL-12p40 via stem-loop structures in their 3’ UTR. Regnase-1 has an RNase activity, and is essential for inhibiting the development of autoimmune inflammatory diseases in mice. We found that TLR stimulation rapidly induces Regnase-1 degradation via phosphorylation by the IkB kinases to stabilize Il6 mRNA. This regulation is important for facilitating rapid and robust production of IL-6 in response to pathogen infection. Furthermore, Regnase-1 mRNA is induced in the later stage of inflammation by a mechanism relaying on the Regnase-1-mediated suppression of self mRNA. I would like to discuss the molecular mechanisms of mRNA degradation by Regnase-1 and how it regulates inflammation.

1. Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez Cuellar E, Kuniyoshi K, Satoh T, Mino T, Suzuki Y, Standley DM, Tsujimura T, Rakugi H, Isaka Y, Takeuchi O and Akira S Malt1-Induced Cleavage of Regnase-1 in CD4+ Helper T Cells Regulates Immune Activation Cell, In press

2. Iwasaki H, Takeuchi O*, Teraguchi S, Matsushita K, Uehata T, Kuniyoshi K, Satoh T, Saitoh T, Matsushita M, Standley DM, Akira S* (*correspondence). The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol. 12, 1167-75 (2011)

3. Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell 140, 805-820 (2010)

4. Matsushita K*, Takeuchi O*, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H & Akira S (*equal contribution) Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185-90 (2009)

Osamu Takeuchi Professor Institute for Virus Research, Kyoto University Address: 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan Phone: +81-75-751-4024 Fax:+ 81-75-761-5766 E-mail: otake@virus.kyoto-u.ac.jp http://www.virus.kyoto-u.ac.jp/Lab/Takeuchi_HP/index.html

Brief CV 1995 M.D., Osaka University Medical School 2001 Ph.D., Graduate School of Medicine, Osaka University 2002-2003 Postdoctoral Fellow, Dana-Farber Cancer Institute 2004-2006 Assistant Professor, Department of Host Defense, RIMD, Osaka University 2007-2011 Associate Professor, Department of Host Defense, RIMD, Osaka University 2007-2011 Associate Professor, Laboratory of Host Defense, IFReC, Osaka University 2012- Professor, Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto

University

Session 3 Cellules Natural Killer, Innate Lymphoid Cells et Immunité

Innée

Eric Vivier Aix Marseille Université

Centre d’Immunologie de Marseille-Luminy Institut Universitaire de France

Natural Killer (NK) cells are lymphocytes of the innate immune system, involved in the elimination of tumors and microbe-infected cells. NK cells sense their cellular targets via inhibitory receptors that recognize surface molecules expressed at steady-state and via activating receptors that recognize stress-induced molecules. NK cells thus express an array of receptors which detect these molecular changes and which trigger cell-mediated cytotoxicity and cytokine production when engaged. In addition NK cells can kill target cells by antibody-dependent cell cytotoxicity if the cells have been tagged by antibodies. There is an increasing interest in NK cells in the basic and clinical research communities. In this context, clinical trials based on the manipulation of NK cells are developed, in particular with the first anti-KIR monoclonal antibodies. The development of innovative therapies based on the manipulation of NK cell recognition strategies for fighting cancer provides the proof-of-principle that explorations of NK cell function thus lead to therapeutic applications. In addition, the dissection of NK cell biology has contributed to identify novel cell subsets called Innate Lymphoid Cells (ILCs), that are present in many tissues including gut and lung, shedding new light of the organization of the immune response in mammals.

Eric Vivier Professor of Immunology (PU-PH), Aix Marseille Université Director of the Centre d’Immunologie de Marseille-Luminy Member of the Institut Universitaire de France

Doct. Vet. Medicine (DVM), Ecole Nationale Vétérinaire, Maisons-Alfort Education

Ph.D, and HDR, University Paris XI Post-doc: Harvard Medical School

Professor of Immunology (PU-PH), Aix Marseille Université Current Position

Director of the Centre d’Immunologie de Marseille-Luminy Member of the Institut Universitaire de France

244 publications, H-factor: 64 Publications

European Research Council advanced grant Selected funding

1999-present: Cofounder of Innate Pharma SA Scientific boards

2008-present: Member of tbe ITMO council: Hematology, Immunology, Pneumology 2010-present: Member of tbe European Research Council Starting Grant Panel

Science Signaling, Frontiers in NK cell biology, Inter. Immunol. Editorial Boards

1996: Prix Pyrénées Orientales de la Ligue Nationale contre le Cancer Selected Awards

1999: Lauréat des Tremplins Rhône-Poulenc pour la Création d'Entreprise 1999: Lauréat du Concours National pour la Création d'Entreprise 1999: Prix Lucien Tartois de la Fondation pour la Recherche Médicale 2003: Prix Jacques Oudin de la Société Française d’Immunologie et du LFB 2004: Prix Var – Dr Joseph Amalric de la Ligue Nationale contre le Cancer 2004: European Federation of Immunological Societies / Deutsche Gesellschaft fûr Immunologie Award 2008: Award Fondation Del Duca – Académie des Sciences 2010: Cancerology Award – Académe des Sciences (Grand Prix Turpin) 2010: European Research Council Advanced Grant 2010: Grand Prix Charles Oberling in Cancerology

Innate immunity, Natural Killer cells, Cancer treatment Research Interests

http://www.ciml.univ-mrs.fr/science/lab-eric-vivier/experts

Session 3

In vivo roles of dendritic cells expressing a chemokine receptor, XCR1

Tsuneyasu Kaisho

Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan

Dendritic cells (DCs) are professional Ag presenting cells linking innate and adaptive immunity. DCs consist of various subsets including plasmacytoid DC (pDC) or CD8α+ DC and these DC subsets exert the subset-specific functions important for immune regulation. In mice, splenic CD8α+ DC is characterized by high ability to produce proinflammatory cytokines, to ingest necrotic cells and to cross-present antigens for inducing CD8 T cell responses. But, it still remains largely unknown how this DC subset is involved in various immune responses or inflammatory processes in vivo. In order to address this issue, we have established the in vivo system for tracking or ablating this DC subset in mice. A chemokine receptor, XC chemokine receptor 1 (XCR1), is highly and selectively expressed in CD8α+ DC. We have generated the mutant mice in which the XCR1 coding region was replaced with the gene for human diphtheria toxin receptor (DTR) and venus fluorescent protein. In the mice, venus+ cells were found in 70-80% of splenic CD8α+ DC. In response to Toll-like receptor (TLR) stimuli, the venus+ CD8α+ DC showed much higher ability to produce IL-12 than venus- CD8α+ DC, indicating that XCR1 expression links with functional maturation. Venus+ DC was also found mainly among splenic CD8α+ DC-related CD103+CD11b- DC in lymph nodes and peripheral tissues such as mucosal tissues or skin. However, other cells including lymphocytes, NK cells, monocytes and monocyte-derived DC were negative for venus. Venus+ cell ablaion demonstrated that XCR1-expressing DC is critical for dsRNA- or listeria-induced CD8 T cell responses. Meanwhile, CD4 T cell responses were rather exaggerated. By using the mutant mice, we have found the critical roles of XCR1-expressing DC in maintaining immune homeostasis. Further analysis on such mice will be presented. T. Kaisho, T. Tanaka. Turning NF-κB and IRFs on and off in DC. Trends Immunol. 29:329, 2008. C. Yamazaki et al. Conservation of a chemokine system, XCR1 and its ligand, XCL1, between human and mice. Biochem. Biophys. Res. Commun. 397:756, 2010. Sasaki et al. Spi-B is critical for plasmacytoid dendritic cell function and development. Blood 2012, 120:4733-4743. T. Kanaya et al. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat Immunol. 13:729, 2012. C. Yamazaki et al. Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. J. Immunol., in press. K. Shimizu et al. Invariant NKT cells induce plasmacytoid DC cross-talk with conventional DCs for efficient memory CD8+ T cell induction. J. Immunol., in press.

Tsuneyasu Kaisho Professor IFReC, Osaka University Address: Yamadaoka 3-1, Suita, Osaka 565-0871, Japan Phone: +81 (0)6 6879-4949 Fax: +81 (0)6 6879-4950 E-mail: tkaisho@ifrec.osaka-u.ac.jp http://immreg.ifrec.osaka-u.ac.jp

Date of Birth: September 1, 1959 Education: Undergraduate:1978-1984 Osaka University, School of Medicine, obtained M.D. in 1984 Graduate:1986-1990 Osaka University, Graduate School of Medicine, obtained Ph.D. in 1990 Research Appointment: 1984-1986 Physician, Osaka University Hospital and National Osaka-Minami Hospital, Osaka, Japan 1990-1994 Research Associate, Osaka University Medical School, Osaka, Japan 1994-1997 Postdoctoral fellow, Genetic Institute, University of Cologne, Cologne, Germany. 1997-1999 Research Associate, Hyogo College of Medicine, Hyogo, Japan 1999-2004 Associate Professor, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 2002-2011 Team Leader, Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology (RCAI), Kanagawa, Japan 2011-present Professor, Laboratory for Immune Regulation (the Kishimoto Foundation), World Premier International Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan Involved in the research on the molecular and cellular mechanisms on dendritic cell functions. Award Japan Immunology Society Award 2009

Session 3

ER, phagosomes and cross presentation in dendritic cells

Sebastian Amigorena Institut Curie, INSERM U932, Immunité et Cancer

Dendritic cells represent a highly specialized hematopoietic lineage, whose main role is to sense infections in tissues and to activate specific T lymphocytes in lymphoid organs to mount immune responses adapted to the threat. To activate T lymphocytes, dendritic cells need to present peptides derived from infectious antigens on MHC molecules on their plasma membrane. There are two main intracellular sites of peptide loading on MHC molecules: the endocytic pathway for class II and the ER for class I MHC molecules. Because of this localization, the former are mainly (not exclusively) loaded with peptides cleaved by lysosomal proteases from internalized antigens. Peptides to be loaded on class I MHC are mainly derived from proteins that are being translated in the cytosol and are cleaved by the proteasome, before translocation into the ER by dedicated TAP1/2 transporters.

In most cells types, the interchange of cargo and membranes between the two compartments is very limited. In dendritic cells, however, ER proteins are quite abundant in phagosomes. We showed recently that Sec22b controls the delivery of a subset of ER resident proteins to phagosomes. In the absence of Sec22b, the abundance of several ER residents in phagosomes is reduced, causing a defect in antigen cross presentation. Intriguingly, we also observed a marked acceleration of phago-lysosome fusion in the Sec22b-silenced dendritic cells, suggesting that the presence of ER in phagosomes delays phagosome maturation. Finally, reduced levels of Sec22b impaired antigen export from endosomes to the cytosol, suggesting a molecular link between export and the presence of ER-derived proteins in phagosomes.

Sebastian Amigorena Institut Curie, Unité INSERM 932 Address : 26, rue D’Ulm, 75005 Paris, France Phone : +33 (0)1 56 24 67 11/14 E-mail : sebastian.amigorena@curie.fr

EDUCATION, POSITIONS, MENTORING and PUBLICATIONS Education and positions Director of the Immunology Department (INSERM Unit 932, Immunity and Cancer), Institut Curie, Paris, 2003 Directeur de Recherche de Classe Exceptionnelle, CNRS, 2010 Postdoctoral Fellow, Cell Biology Dept, Yale University Shool of Medicine, New Haven, CT, 1992 PhD, Biochemistry, Immunology, University Paris VII, Paris, France, 1990 Professional memberships Member of the French “Académie des Sciences” Member of the EMBO Member, American Association of Immunology Member, French Association of Immunology Mentoring 7 PhD students, 26 post doctoral fellows

CVs (Chairpersons)

Chairperson

Jean-Marc Reichhart Professor IUF-UdS IBMC UPR 9022 CNRS Université de Strasbourg

Jean-Marc Reichhart defended a PhD in Embryology at the University Louis Pasteur of Strasbourg in 1977 and started a small group working on the immune system of Insects in 1985. In 1991, he was appointed Professor in Developmental Biology at the University of Strasbourg and in 1996, his interest in the mechanisms of early development led to the discovery of the implication of the Toll pathway (already known for its role in the setting up of the dorso-ventral axis in the Drosophila embryo) in the antifungal response of the adult fly. This work was the breakthrough that led to the discovery of the human homologues of Toll, the Toll-Like-Receptors (TLRs). In 1998-1999, during a sabbatical leave in the Department of Genetics of Cambridge (UK), he discovered that a mutation called “necrotic”, in a serine protease inhibitory protein (a serpin) leads to constitutive activation of the Toll pathway. This work indicated that the Toll receptor in the fly is engaged, as in the early embryo, by an endogenous ligand. He is the director of the CNRS research Unit UPR 9022 and since 2000 his group studies the Innate Immune System in an evolutionary perspective, using the fruit fly as a model system and focusing on host-pathogen interactions. He was nominated at the “Institut Universitaire de France” in 2008 and elected EMBO member in 2009.

For JM Reichhart, « basic research, using model systems such as the fruit fly, has led to tremendous advances in many fields. It has completely changed our view of the human immune system and has opened new perspectives in the field of modern medicine ».

Chairperson

Jean-Luc Imler Professor of Cell Biology CNRS research unit UPR9022 Institut de Biologie Moléculaire et Cellulaire Université de Strasbourg

Jean-Luc Imler is Professor of Cell Biology at the University of Strasbourg, and group leader in the CNRS research unit UPR9022 at the Institut de Biologie Moléculaire et Cellulaire. After obtaining his Master Degree in Life Science from Agro Paris Tech in 1985, he joined the department chaired by P. Chambon at the University Louis Pasteur in Strasbourg for his PhD, which he obtained in 1988. He then worked on cytokine signalling in the Molecular Biology department of the DNAX Research Institute in Palo Alto, California for three years, before returning to France in 1992 to work in the biotech company Transgene. He joined the UPR9022 CNRS department to work on innate immunity in 1994 and has been a close collaborator of Jules Hoffmann since then. The group of J.-L. Imler has been focusing in the past ten years on antiviral immunity in the drosophila model. J.-L. Imler is collaborating with the groups of B. Beutler (Dallas, USA), S. Akira (Osaka, Japan) and J. Marques (Belo Horizonte, Brazil) to translate the findings of his group to mammalian models, and to mosquitoes transmissing arthropod-borne viruses like Dengue to humans.

Chairperson

Serge Potier Professor of Genetics Director of the Doctoral School of Health and Life Sciences vice president in charge of « Investissements d’Avenir » University of Strasbourg

Serge Potier, Professor of Genetics, is Director of the Doctoral School of Health and Life Sciences and vice president in charge of « Investissements d’Avenir » in the University of Strasbourg. After a PhD thesis in genetics obtained in 1986, he got a Professor position in Université Louis-Pasteur de Strasbourg in 1989 in charge of undergraduate and graduate genetics teaching. He published about 80 articles on different aspects of genetics and molecular biology of yeasts : osmotic stress, cations transport, gene regulation, chromosomes rearrangements, genome sequencing, genome evolution, Genolevures project. During the period 2001-2009, he was Dean of the Life Sciences Faculty and in 2001-2012 he was director of the laboratory « Génétique Moléculaire, Génomique, Microbiologie » in Strasbourg University.

Note

Note

JSPS Strasbourg Office 42a, Avenue de la Forêt-Noire

67000 Strasbourg, France Tel : +33 (0)3 68 85 20 17 Fax : +33 (0)3 68 85 20 14 http://jsps.unistra.fr/