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Immune Regulation and Tolerance

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Immune Regulation and Tolerance Mechanisms of unresponsiveness: Immunological Ignorance Immune Regulation Normal response and Proliferation and Tolerance differentiation Mechanisms of Antigen/lymphocyte barrier unresponsiveness Mechanisms of Tissue abnormalities contributing to release and Yong-Rui Zou (Oct. 2005) autoimmunity presentation of self antigens. [email protected] Disease models Sympathetic ophthalmia, experimental allergic encephalomyelitis (EAE) Immunoregulation: A balance between activation and Mechanisms of unresponsiveness: suppression of effector cells to achieve an efficient Central tolerance in B and T cells (I): Clonal Deletion immune response without damaging the host. Self antigen presented in generative Activation (immunity) Suppression (tolerance) lymphoid Deletion of immature organs lymphocytes strongly recognizing self antigens autoimmunity immunodeficiency present in generative organs Lymphoid precursor Significance: The induction of tolerance may be Survival of clones which are only moderately exploited to prevent graft rejection, to treat autoimmune responsive to self antigens and allergic diseases, and to prevent immune responses present in generative in gene therapy. organs; forms T/B cell repertoire Important features of immunoregulation: 1. Antigen specific; affects T or B lymphocytes Science 298:1395 (2002) 2. Tolerance vs. activation? Determined by the nature of antigen and associated stimuli, and when and where the antigen is encountered Immunity 23:227 (2005) 1 Mechanisms of unresponsiveness: AIRE: Autoimmune regulator. Peripheral tolerance in B cells (I): Anergy Immunogenic signaling Tolerogenic signaling • Transcription factor. • Expressed at a high level by thymic medullar epithelium Acute Chronic cells. antigens antigens CD40L • Autosomal recessive mutation leads to autoimmune LPS polyendocrine syndrom - type 1 (APS-1). CD40 CD40 TLR4 • Inactivation of aire abolishes expression of some tissue TLR4 BCR BCR Fcγ2b specific genes in the thymic medulla. NFκB NFκB • AIRE deficiency impairs antigen-presentation ability of Ca++ Ca++ medullary epithelial cells. Growth genes Inhibitory genes Anergic B cells can respond to “Stronger” antigens Oligovalent self antigens Multivalent foreign antigens Constitutively exposed Acutely exposed aire -/- Anergic Anergic B cell B cell WT Remains anergic Activated Mechanisms of unresponsiveness: Mechanisms of immune tolerance Central tolerance in B cells (II):Receptor editing Peripheral B cell Tolerance (II): Follicular exclusion pre-B bone marrow B follicle T cell zone 2% κ rearrangement 10% B B220 Maturation of clones: further Moma-1 rearrangement • Non-reactive to soluble- Spleen • low-affinity to soluble- artery • self-reactive to TCR Self monovalent- immature antigens in bone marrow antigens B 90% 2 Mechanisms of unresponsiveness: The two-signal requirement for T cell activation Peripheral tolerance in B cells (II): Follicular exclusion Microbial antigen presented by APC TCR MHC - B cells binding to autoantigens in the periphery Signal 1 may be excluded from follicles. APC - Excluded B cells undergo apoptosis independent Signal 2 of Fas and T cells. Costimulatory B7 Receptor (CD28) - Rapid elimination depends on the presence of a normal repertoire of B cells. competition between B cells for BAFF T wo- si g n al r e q u i r em ent f or lym p ho cyt e ac t iva ti on • N a ïv e l ympho c y t e s ne e d t w o s i gn a l s t o i n i t ia t e re s pon ses BAFF: B-cell activating factor belonging to TNF family. • S ign al 1: a n t ig e n re c ogn i t i on • TNF family proteins, expressed by stromal cells Æ En s ur e th at th e i m m un e re s pon s e is an ti gen- s p e c i f i c in the spleen. • Plays a critical role as a survival factor for mature B cells. • S ign al 2: mi c r obe s or s ub st an c e s produ c ed dur i ng i nna t e imm une • BAFF transgenic mice develop autoimmune disorder. r es pon s e s t o m ic robe s Æ En s ur e th at th e i m m un e sy ste m r es pond s to mi c r obe s and no t t o ha r m les s a n t ig e n i c s ub st anc e ( S e c ond s ign al s for T c e l l s are co stim ul at or s on A P C s a nd cy t ok i ne s produ c ed by A PCs .) Self antigen crosslinks BCR with no self reactivity Self antigen crosslinks Mechanisms of unresponsiveness: BCR strongly BCR weakly Peripheral tolerance in T cells (II): Anergy Pretreatment Stimulation T cell of T cells with antigens response B7 CD28 B7 CD28 18-24 hr CD28 B7 CD28 Death Survival Death Rescued by increased 18-24 hr BAFF production or reduced BAFF consumption Nature 435:590 (2005) 3 Molecular basis of anergy in T lymphocytes How do T cells choose between CD28 and CTLA-4? TCR CD3ζ P Zap 70 PROXIMAL EVENTS: • Kinetics: B7 on APCs engages CD28 early, CTLA-4 late in T - Reduced tyrosine cell responses. phosphorylation - Reduced Ca++ influx • Level of B7 expression on APCs: low levels favor CTLA-4 engagement (high affinity receptor). GROWTH FACTORS NUCLEAR EVENTS: - no induction of NFκB CELL JNK activities CYCLE Regulation of T cell homeostasis during immune responses Co-stimulatory pathways Anergy T cell • CD28 interacts with CD80 (B7-1) CD86 (B7-2) to expansion initiate T cell responses. B7 CTLA-4 Preferentially expressed in naive T cells • ICOS (CD28 homolog) stimulate effector T cell responses. Activated T cells Apoptosis express CTLA-4 Preferentially expressed in activated T cells Magnitude ofT cell response Surviving B7 CD28 Activated T cells are memory cells deprived of antigen • CTLA-4 and PD-1 inhibit T cell activation and other stimuli T cell activation Time after antigen exposure Mechanisms of immune tolerance: CTLA-4-/- T cells resist tolerance induction Peripheral T cell tolerance (III): Activation-induced cell death (AID) Naïve Tolerated To prevent over-expansion of the activated T cells Control homeostasis of T cell responses Days 4 T cell mediated suppression -/- Enhanced proliferation of activated CTLA4 T cells MBP-TCR In Rag-/- MBP MBP-TCR In wildtype MBP MBP-TCR In Rag-/- MBP CD4+ T cells Pathways of apoptosis in T cells Regulatory T cells (Treg) in self tolerance Release of Elimination mitochondrial of Antigen and cytochrome c, activation of • Phenotype and functions: other signals “Passive” caspase-9 cell death (death by ¾ CD4+CD25+ cells, develop in the thymus. B7 CD28 neglect) ¾ Recognize self-antigens. T cell proliferation ¾ Express Foxp3. Foxp3 mutation causes the early onset of fatal autoimmune disorder observed in scurfy mutant mice and human IL-2 IPEX patients (immune dysregulation, polyendocrinopath, FasL Persistence Fas enteropathy, X-linked syndrome). of antigen, Activation of repeated caspase-8 ¾ Prevent T-cell activation; supress cell proliferation and IL-2 production. stimulation Activation induced cell death Mechanisms of immune tolerance: Peripheral T cell tolerance (IV): Suppression by Treg Neonate thymectomy --> Autoimmune diseases 1. The disease is transferable by T cells. 2. The disease can be prevented by delayed thymectomy or by transplantation of normal CD4+ T cells. Science (2003) 299:1057 5 • Foxp3 is expressed specifically in TR Conclusions: Tolerance vs. Immunity • Immune responses are the outcome of a balance between the need to make a protective response and the need to maintain self-tolerance + • Expression of Foxp3 converts naïve CD4 T cells to TR • Mechanisms of unresponsiveness: – Central tolerance: Deletion; Receptor editing – Peripheral tolerance: Clonal ignorance; Clonal deletion; Anergy; Suppression Role of cytokines in suppression Mechanisms of immune tolerance: of cell-mediated immune responses Central Peripheral Antigen T cell proliferation Effector functions recognition and differentiation of T cells IL-12 Effector T cells Activated CD4+CD8- CD4+CD8- Th (TH1) macrophages APC Naïve T cell + + IFN-γ CD4 CD8 CD4-CD8+ CD4-CD8+ Tc IL-10 inhibits TGF-β inhibits IL-4 inhibits IL-10, TGF-β Cytokines Pro/Pre Plasma Functions of APCs: T cell action of inhibit B(IM) B(M) produced by B Cell IL-12 secretion, B7 proliferation IFN- macrophage suppressor γ expression activation T cells Clonal deletion Clonal deletion AID Receptor editing Receptor editing Treg suppression Suppressor T cells Anergy Mechanisms of immune tolerance: Peripheral T cell tolerance (IV): Suppression by Treg B7 CD28 T cell MHC TCR DC IL-10 IDO TGF-β B7 CTLA-4 Treg Indoleamine deoxygenase (IDO) IFN-γ Cleavage of tryptophan 6.
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