negative regulation of immune responses by various mechanisms
TRANSCRIPT
Negative regulation of immune responses by various mechanisms
NEGATIVE REGULATION OF T CCELL RESPONSES
Days5 10 15 20 25 30
Naive lymphocytes
Number of antigen specific cells
Primary effectors
Secondary effectors
Memory
DIFFERENTIATION
AICD
EXPANSION
AICD
MEMORY
AICDActivation Induced Cell Death
Elimination of effector T cells at the end of the immune response
Activation-induced cell death (AICD)
Sustained T cell activation induces pro-apoptotic signals
Expression of Fas, FasL, Bad, Bax is increased – CELL DEATHExpression of Bcl-2 is decreased – SURVIVAL decreased
Signaling Pathways of AICD
Ligand binding to TNFR1 és TNFR2 receptors triggers pro- and anti-apoptotic signalling pathways
C D 8 + Tc
F a s
C D 4 + T h 1
F a s L
C D 4 +
T h 1
A P C
B
THE ROLE OF CD4+ T CELLS IN APOPTOSISFas receptor – Fas ligand interactions
T CELL HOMEOSTASIS SHUT OFF IMMUNE RESPONSES
REGULATION OF T CELL RESPONSES BY INHIBITORY CO-RECEPTORS
A B7 : CD28 receptor family
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T cell anergy. An antigen presented by costimulator-expressing antigen-presenting cells (APCs) induces a normal T cell response. If the T cell recognizes antigen without strong costimulation, the T cell receptors may lose their ability to deliver activating signals, or the T cell may engage inhibitory receptors, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4), that block activation.
Immunological Tolerance and Autoimmunity : Self-Nonself Discrimination in the Immune System and Its FailureAbbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 9, 171-187
Copyright © 2014 Copyright © 2014, 2011, 2009, 2006, 2004, 2001 by Saunders, an imprint of Elsevier Inc.
Anergy
CD28
Activated T cell
CD28 cross linked by B7
Costimulatory molecules associatealso with inhibitory receptors
CTLA-4 binds CD28 with a higher affinity than B7 molecules
/CTLA-4
B7
CD28
T cell
B7
2 2Signal 1 +
Co-stimulation induces CTLA-4DELAYED EXPRESSION
The lack of signal 2 to the T cell shuts down the T cell response
Cross-linking of CTLA-4by B7 inhibits co-stimulationand inhibits T cell activation
- - -- -
B71/2
TAPC
CD28 activation
CTLA-4
ITIM
NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4
LATE EXPRESSION
HIGHER AFFINITY TO B7 THAN TO CD28
NEGATIVE REGULATION OF IMMUNE RESPONSES BY REGULATORY T CELLS
The main role of regulatory T cells
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Central T cell tolerance. Strong recognition of self antigens by immature T cells in the thymus may lead to death of the cells (negative selection, or deletion), or the development of regulatory T cells that enter peripheral tissues.
Immunological Tolerance and Autoimmunity : Self-Nonself Discrimination in the Immune System and Its FailureAbbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 9, 171-187
Copyright © 2014 Copyright © 2014, 2011, 2009, 2006, 2004, 2001 by Saunders, an imprint of Elsevier Inc.
Regulatory T cells develop in the tymus(Natural Tregs, Sakaguchi)
Development of the CD25+CD4+ Development of the CD25+CD4+ regulatory T cell lineageregulatory T cell lineage
TCR as polymorphic as for CD25- cellsTCR as polymorphic as for CD25- cellsSpecific to self antigens, MHC II restrictedSpecific to self antigens, MHC II restrictedRequires IL-2, Requires IL-2, Co-stimulation, CD28, B7Co-stimulation, CD28, B7
Foxp3 is a master regulatorFoxp3 is a master regulatortransforms CD25 statustransforms CD25 status
SchwartzSchwartzNat Immunol Nat Immunol 20052005
Hassall’s corpuscles instruct dendritic cells to induce Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymusCD4+CD25+ regulatory T cells in human thymus
TSLP:TSLP: Thymic stromal lymphopoietin (activates human DC) Thymic stromal lymphopoietin (activates human DC)DC-LAMP:DC-LAMP: Dendritic cell lysosomal-associated Dendritic cell lysosomal-associated membrane proteinmembrane protein Watanabe et al. Nature 436, 1181Watanabe et al. Nature 436, 1181
Development and function of regulatory T cells. CD4+ T cells that recognize self antigens may differentiate into regulatory cells in the thymus or peripheral tissues, in a process that is dependent on the transcription factor FoxP3. (The larger arrow from the thymus, compared to the one from peripheral tissues, indicates that most of these cells probably arise in the thymus.) These regulatory cells inhibit the activation of naive T cells and their differentiation into effector T cells, by contact-dependent mechanisms or by secreting cytokines that inhibit T cell responses. The generation and maintenance of regulatory T cells also require interleukin-2 (not shown). APC, Antigen-presenting cell.
I
Natural and induced Tregs
nTregnTreg
THYMUSTHYMUS
PERIFÉRIAPERIFÉRIAFoxP3+
FoxP3-
IL-2/TGFβ MaintenanceMaintenance
nTregnTreg
Effector T
IL-10/IL-35/TGFβSupressionSupression
Effector T
DC
FoxP3-Tr1Tr1
IL-10/ TGFβ
IL-10
SuppressionSuppression SuppressionSuppression
FoxP3+Th3Th3
TGFβ
IL-10/ TGFβ
mTEC
CD4+TCD4+TFoxP3-
iTregiTreg
FoxP3+
PERIPHERYPERIPHERY
ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLSORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS
FUNCTIONS OF REGULATORY T CELLSFUNCTIONS OF REGULATORY T CELLS
•Maintenance of peripheral tolerance
•Prevention of autoimmunity
•Limiting inflammatory processes (asthma, inflammatory bowel diseases)
•Inhibit protection against infectious diseases
•Limit immune responses to tumors
MECHANISM
Intrinsic and extrinsic regulation
Various inhibitory mechanisms
Cell contacts – Cytokines
Interaction with the target effector T cells
REGULATORY T CELLSREGULATORY T CELLS
Homeostatic regulationHomeostatic regulation
THYMUSTHYMUS
Natural– nTregNatural– nTreg
PERIPHERYPERIPHERY
Induced – iTregInduced – iTreg
Induced regulationInduced regulationTregTreg
Autoimmune diseasesAutoimmune diseases Transplantation toleranceTransplantation tolerance
Malignant diseasesMalignant diseases
DCDC
AKTIVATIONAKTIVATION INDUCTIONINDUCTION
COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND DENDRITIC CELLS DENDRITIC CELLS
TregTregCD25IL-2Rα
CTLA4B7 ligand
GITR
MARKERS OF THYMUS DERIVED NATURAL Treg CELLS
CD127IL-7Rα ↓
Treg differentiation, maintenance, functionTranscription factor – many target genesFoxP3 by itself is not sufficient to confer suppressive functionsTGFβ does not induce regulatory functions
FoxP3
CD4+CD25+FOXP3+
REGULATORY T CELLS
MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONSFUNCTIONS
IL-35
Inhibitory cytokines
TGFβ
IL-10
Cytolysis
Metabolic disturbance Inhibition of dendritic cell differentiation
Reduced cytokine production (IL-2)Reduced cytokine production (IL-2)Peri-cellular adenosinePeri-cellular adenosine
cAMP transfercAMP transfer
Indolamine-2,3 dioxigenaseIndolamine-2,3 dioxigenaseLAG-3 – CD4 homologueLAG-3 – CD4 homologue
CELL SURFACE ENZYMES OF REGULATORY T CELLS CELL SURFACE ENZYMES OF REGULATORY T CELLS PRODUCE EXTRACELLULAR NUCLEOTIDESPRODUCE EXTRACELLULAR NUCLEOTIDES
Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase
Ecto-5’-nucleotidase
EBI3Ebstein-Barr virus induced gene 3
IL-27 and IL-35
Naiv T sejtek toborzása, aktiválása, polarizálása
CD4+CD25- effektor sejtek A2A receptort fejeznek ki
Peri-cellular/Szupresszív
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Inhibition of dendritic cell functions by Treg cells
Sakaguchi, Nat Immunol, 2010
In the absence of Treg cells the effector T-cells act as adjuvants as they promote DC activation through increasing the expression of MHC and co-stimulatory molecules and the production of inflammatory cytokines.
CTLA-4 regulates Treg functions through inhibiting CD80 and CD86 mediated co-stimulatory signals resulting in reduced inflammatory cytokine production. CTLA-4 also induces indoleamine-2,3-dioxygenase (IDO) enzyme activity that has immune suppressive effects.
CTLA-4 is an important membrane protein that through Treg cell can regulate antigen presenting cell functions
Blocking CTLA-4 tissue specific autoimmune disease, inflammatory bowel disease (IBD) in mice.
•A regulátor T-sejtek funkcionális aktivitásának befolyásolása komoly terápiás Hatással lehet számos autoimmun betegség és fertőző betegség kezelése esetén
• Transzplantáció
•Tumor therapy
• How to do it? In vitro Treg expansion…. ?
•Blocking of inhibitory cell surface molecules with antibodies or otherwise
A klinikai alkalmazás lehetőségei:
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TregTreg
RESTING Foxp3+ Treg
THYMUSTHYMUS
nTreg
PERIPHERYPERIPHERY
iTregiTreg
ACTIVATED Foxp3+ Treg
Local effectsLocal effectsPAMP, TLR, NLR, RLRPAMP, TLR, NLR, RLRInflammation, IFN, TGFInflammation, IFN, TGFββT cell activationT cell activation
Treg activationCTLA4, GITR, IL-10, CTLA4, GITR, IL-10,
IDO, PD-1/PD-LIDO, PD-1/PD-L
TregTreg TregTreg
TOLEROGENIC RESPONSE HELPER RESPONSE
Local tolerance Local immune response
Treg re-programingIL-6, IL-1IL-6, IL-1
DEVELOPMENT OF REGULATORY T LYMPHOCYTES IS DEVELOPMENT OF REGULATORY T LYMPHOCYTES IS ENVIRONMENT DEPENDENTENVIRONMENT DEPENDENT
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