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Negative regulation of immune responses by various mechanisms

Negative regulation of immune responses by various mechanisms. ITAM-ITIM. ITIM- mediated inhibition ITIM recruited phosphatases inhibit the ITAM-induced kinase cascade. B cell regulation CD22. Sialic acid. B cell regulation Fc γ RIIb. Fc γ RII mediated B cell feedback regulation. Ag.

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Negative regulation of immune responses by various mechanisms

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  1. Negative regulation of immune responses by various mechanisms ITAM-ITIM

  2. ITIM- mediated inhibition ITIM recruited phosphatases inhibit the ITAM-induced kinase cascade

  3. B cell regulation CD22

  4. Sialic acid

  5. B cell regulation FcγRIIb FcγRIImediated B cellfeedbackregulation Ag Ag B cell FcγRIIb B cell FcγRIIb Phosphorilated ITIM motifs on FcγRIIb recruits phosphatases to interfere signal transduction Inhibition of the signal transduction of B cell receptor

  6. T cellregulationCTLA4, PD-1 (ITIM Like)

  7. NK cell regulation MHCI

  8. ITAM/ITIM-mediated regulation is a general process ITAM and/or ITIM containing receptors 2B4/CD244/SLAMF4ILT7/CD85gBLAME/SLAMF8ILT11/LILRA5BTLAImmunoreceptor Array KitCD3Integrin alpha 2b beta 3CD3 epsilonIntegrin beta 3/CD61CD5KIR/CD158CD6KIR2DL1/CD158aCD23/Fc epsilon RIIKIR2DL2/CD158b1CD28KIR2DL3/CD158b2CD31/PECAM-1KIR2DL4/CD158dCD72KIR2DL5/CD158fCD84/SLAMF5KIR2DS1/CD158hCD229/SLAMF3KIR2DS4/CD158iCD300a/LMIR1KIR2DS5/CD158gCD300b/LMIR5KIR3DL1CD300c/LMIR2KIR3DL2/CD158kCD300e/LMIR6KIR3DL3/CD158zCD300f/LMIR3KIR3DS1/CD158e2CEACAM-1/CD66aKLRG1CEACAM-3/CD66dLAIR1CLEC-1LAIR2CLEC-2LIR-8/CD85cCLEC-2AMDL-1/CLEC5ACRACC/SLAMF7MICL/CLEC12ACTLA-4NFAM1DCAR/CLEC4BNKp30/NCR3DCIR/CLEC4ANKp44/NCR2Dectin-1/CLEC7ANKp46/NCR1DNAM-1/CD226NKp80/KLRF1Fc epsilon RI alphaNTB-A/SLAMF6 Fc epsilon RI beta/MS4A2PD-1Fc gamma RIII (CD16)PDCD6FCAR/CD89PILR-alpha Fc gamma RI/CD64Siglec-2/CD22Fc gamma RII/CD32Siglec-3/CD33Fc gamma RII/RIII (CD32/CD16)Siglec-5/CD170Fc gamma RIIA/CD32aSiglec-5/Siglec-14Fc gamma RIIB/CD32bSiglec-6/CD327Fc gamma RIIB/C (CD32b/c)Siglec-7/CD328Fc gamma RIIC/CD32cSiglec-8Fc gamma RIIIA/CD16aSiglec-9Fc gamma RIIIB/CD16b Siglec-10FCRL1/FcRH1Siglec-11FCRL2/FcRH2Siglec-14FCRL3/FcRH3Siglec-16 FCRL4/FcRH4Siglec-EFCRL5/FcRH5Siglec-FFCRL5/FCRL3Siglec-GFCRL6/FcRH6 Siglec-HG6bSIRP beta 1/CD172bILT2/CD85jSLAM/CD150ILT3/CD85kTIGITILT4/CD85dTREM-3ILT5/CD85aTREML1/TLT-1ILT6/CD85eTREML2/TLT-2

  9. Immune Tolerance

  10. Central and Peripherial tolerance

  11. Central tolerance

  12. SELECTION OF T LYMPHOCYTES IN THE THYMUS AICD – Activation Induced Apoptosis PERIPHERAL TOLERANCE UNDER THE CAPSULE • The primary T cellpool is biasedtoMHC-specificity (V genes) 1-2% foroneallotype • Focusingthe T cellpooltoself MHC recognition(+) • Elimination of useless and selfagressiveclones(-) • CENTRAL TOLERANCE • Focusingthe T cellrepertoireforrecognition of non self • CD4+ and CD8+ T cellusethesame TCR repertoire • Individualized T cellrepertoireavailableintheperiphery • CD4 and CD8 co-stimulatorymoleculesareinvolvedinpositiveselection IL-7-dependent proliferation CORTEX CD4-CD8- DN β+preTα TCRαβ CD4+CD8+ DP TCR(-) sMHC+sP sMHC+fP fMHC+fP selection CORTEX/ MEDULLA   NO  – selection MEDULLA – AICD αβTCR αβTCR CD4+CD8+

  13. SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE POSITIVE SELECTION – Thymic education (no instruction for specificity) Low avidity interaction of MHC - self peptide - TCR Thymic epithelial cells Self peptide composition and concentration (foreign peptides are not present) Low peptide dose induces positive selection – special ligands 80-90% of DN (CD4-CD8-) T cells is NOT positively selected PASSIVE CELL DEATH BY NEGLECTION NEGATIVE SELECTION – Central self tolerance High avidity of MHC - self peptide - TCR interaction Ubiquitous and abundant self antigens are present in the thymus High peptide dose induces negative selection Any thymic antigen presenting cell: epithelial cells, bone marrow-derived macrophages, dendritic cells THE GENERATION OF SELF MHC + FOREIGN PEPTIDE SPECIFIC T CELLS REQUIRES WEAK INTERACTION WITH SELF MHC + SELF PEPTIDE SELF RESTRICTED AND TOLERANT PERIPHERAL T CELL REPERTOIRE PHYSIOLOGICAL TRESHOLD NOT COMPLETE

  14. tissues are represented promiscuous gene expression in thymic epithelial cells AIRE transcriptionfactor autoimmune regulator (AIRE) protein. Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called the autoimmune polyendocrine syndrome (APS).

  15. Peripherial tolerance

  16. Peripherial tolerance deletion, apoptosis

  17. Activation induced cell death

  18. NEGATIVE REGULATION OF T CELL RESPONSES AICD ActivationInducedCellDeath AICD DIFFERENTIATION Naive lymphocytes Memory Primary effectors Secondary effectors Number of antigen specific cells EXPANSION AICD MEMORY

  19. Signaling Pathways of AICD

  20. Ligand binding to TNFR1 és TNFR2 receptors triggers pro- and anti-apoptotic signalling pathways

  21. Elimination of effector T cells at the end of the immune response Activation-inducedcelldeath (AICD) Sustained T cellactivationinducespro-apoptoticsignals Expression of Fas, FasL, Bad, Bax is increased – CELL DEATH Expression of Bcl-2, FLIP is decreased – SURVIVAL decreased

  22. repeated stimulation of T cells by persistent antigens leads to the coexpression of the two molecules, a death- inducing receptor called Fas(CD95) and its ligand, Fas ligand(FasL)

  23. THE ROLE OF CD4+ T CELLS IN APOPTOSIS Fas receptor – Fas ligand interactions T CELL HOMEOSTASIS SHUT OFF IMMUNE RESPONSES

  24. Anergy

  25. A B7 : CD28 receptor family

  26. ABBAS MIT 2013 Pécs

  27. The activation of naiv T cell requires costimultaion Costimulatory molecules are expressed only in professional antigen presenting cells

  28. Anergy Absence of costimulation or Negative signal

  29. TCR activation in the absence of costimulation results in the degradation of key moleclues in TCR signaling

  30. ITIM CTLA-4 NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4 T APC CD28activation B71/2 LATE EXPRESSION CTLA4 has HIGHER AFFINITY TO B7 THAN TO CD28, but the amount of it is limited CTLA4 1. Inhibition of ITAM signaling 2. Competition with CD28

  31. In general the activation of naiv T cells requires DC-mediated antigen presentation

  32. PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY Normal tissue cells do not express MHC class II NO SIGNAL 1. for CD4+ Th activation Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokines NO SIGNAL 2. for CD4+ Th activation Migration of naive T lymphocytes to normal tissues is limited Antigen presenting cells are not activated in normal tissues NO SIGNAL 3. for CD4+ Th activation PERIPHERAL TISSUES TOLERIZE THEMSELVES

  33. NEGATIVE REGULATION OF IMMUNE RESPONSES BY REGULATORY T CELLS

  34. The main role of regulatory T cells ABBAS MIT 2013 Pécs

  35. Sakaguchi 2008

  36. FUNCTIONS 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

  37. Regulatory T cells are normal T cells! MHC/peptide recognition--- self peptides! clonal proliferation, activation... mostly 95% CD4+ helper T cells

  38. Natural regulatory T cell

  39. Development of the CD25+CD4+ regulatory T cell lineage Schwartz NatImmunol 2005 TCR as polymorphic as for CD25- cells Specific to self antigens, MHC II restricted Requires IL-2, Co-stimulation, CD28, B7 Foxp3 is a master regulator transforms CD25 status

  40. Th2 Th1 Th0 Inflammatory cytokines CELLULAR IMMUNE RESPONSE Anti-inflammatory cytokines HUMORAL IMMUNE RESPONSE IL-4, IL-5, IL-10 IFNγ, IL-2, TNF-β/LT EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES IFNγ IL-4

  41. Inducible Treg cells

  42. Sakaguchi 2008

  43. InducibleTreg requires TGF-β, IL2 TGF-β or blocking of TGF-β signals in T cells leads to a systemic inflammatory disease IL-2 receptor is knocked out develop autoimmunity

  44. The dependence of Treg cells on IL-2, which they cannot produce themselves but instead receive fromconventional T cells,provides a negative feedback loop through whichthe ratio between Treg cells and conventional T cells is controlled

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