The two-signal requirement for T cell activation

Transcription

1 Mechanisms of unresponsiveness: Peripheral tolerance in B cells (II): Anergy The two-signal requirement for T cell activation Immunogenic signaling Acute antigens L LPS Chronic antigens Tolerogenic signaling Signal 1 Microbial antigen presented by MHC BCR Ca 2+ NFκB TLR4 BCR Ca 2+ Fcγ2b NFκB TLR4 Signal 2 Costimulatory Receptor (8) Growth genes Inhibitory genes The role of co-stimulation in T cell activation Regulation of T cell homeostasis during immune responses Antigen recognition T cell response Resting : (costimulatordeficient) : increased expression of costimulators, secretion of cytokines 8 of Innate immune response 8 No response T cell proliferation And differentiation Magnitude of T cell response T cell activation T cell expansion 8 CTLA-4 T cells express CTLA-4 Apoptosis T cells are deprived of antigen and other stimuli Time after antigen exposure Anergy Surviving memory cells Role of cytokines in suppression of cell-mediated immune responses Antigen recognition IL-12 Naïve T cell T cell proliferation and differentiation Effector T cells (T H 1) Effector functions of T cells macrophages Immunosurveillance: Tumors which Evolve in Lymphocyte Deficient Hosts are Rejected in Mice 100% RAG-/- Tumor Incidence 0% Tumor (Sarcoma) Incidence is Increased in MCA-treated Lymphocyte Deficient Mice Cytokines produced by suppressor T cells IL-10 inhibits Functions of s: IL-12 secretion, expression TGF-β inhibits T cell proliferation inhibits action of IL-10, TGF-β inhibit macrophage activation Tumor Size Tumor: origin RAG-/- origin Tumors which developed in RAG-/- hosts are REJECTED in Recipients Suppressor T cells Host: RAG-/- 1

2 Immune Surveillance: Tumor Expression of IFNγ Receptor is Required for Lymphocyte-Mediated Tumor Rejection Tumor Size 100% Tumor Incidence after MCA Treatment 0% IFNγR-/- Host: RAG-/ Transplanted tumor IFNγR -/- IFNγR -/- IFNγR-/- transfected transfected with IFNγR with IFNγR CTL 8 CD8 ClassI +peptide Dendritic IMMUNE RECOGNITION Class II + peptide Ag Processing/ presentation of peptides Cross-Priming: Induction of Anti-tumor T cell response IL-2 TH1 L Endocytosis/ phagocytosis Provide T H 1 or 2 Help for B cell Ab Responses Tumor Effector Mechanisms CD8 CTL Can Recognize Class I peptide Complex and Induce Tumor Lysis and Apoptosis Granule exocytosis: Perforin/granzyme CD8 CTL Effector Mechanisms s are -Mediated Effectors TNF (+ other TNF-family members) NO, O2, proteases TH1 L Tumor Class I + peptide Fas -FasL Class II + peptide Cytokine- Mediated GM-CSF TNF Effector Mechanisms Antibody Bound Targets Induce Myeloid Tumor Cytotoxicity Through Fc Receptors +/or Complement Receptors ADCC, phagocytosis, release of inflammatory mediators (NO, O2, proteases, TNF, etc.,) Tumor C3b Tumor Evasion: Two Separate Problems Tumor antigens are not recognized by immune response-poorly immunogenic (Immunologically ignorant). Tumors are resistant to or inhibit immune cytotoxic responses. (active suppression either dampen priming or avoid/inhibit/resist effector cell function). 2

3 Strategies for induction of anti-tumor Immune Responses -Passive- Adoptive transfer of T cells: Antigenic specific T cell clonesrequires HLA-restricted customized therapy or cytokine-enhanced antigen-non-specific T cells (LAK cells). Has worked for EBV lymphoproliferative disorders. Model of Innate Recognition and Initiation of the Adaptive Antitumor Immune Response Monoclonal and engineered antibodies: 1. Humanized/chimeric mabs: Herceptin (anti-her2), Rituxan (anti-0), anti-idiotype (custom therapy), anti-egfr (Erbitux), CAMPATH (anti-cd52), anti-vegf (targets neovasculature, Avastin). 2. Immune conjugates ( smart bombs ) mab-toxin (Mylotarg: anti- CD33 calicheamicin), mab-chemo, mab-isotope (anti-0 Zevalin and Bexxar). danger = invasion (inflam. response) + stress ligands of NKG2D Amplification of innate and link to adaptive response Apoptosis provides antigen delivery to DCs Elimination by adaptive response Monoclonal Antibody Therapeutics in Cancer Functions of Th1 and Th2 cells Type Function Helpful Harmful Rituxan (anti-0) High response rate in B cell lymphoma (>70%). Synergy with chemotherapy or XRT. Recognizes B cell marker regulating B cell activation. Induces growth arrest/apoptosis in vitro. Herceptin (anti-her2) Lower response rate in breast cancer (15%). Synergy with chemo (60%) or XRT. Recognizes EGF-like receptor regulating cellular proliferation (ERBB2). Induces growth arrest/apoptosis in vitro. Th1 IL-2 TNFα Th2 IL-5 IL-6 IL-10 Activate macr ophages, dendritic cells DTH B cell help down-regulate Th1 class swi tching Tb, fungi, Leishmania and other intracell ular bacteria Cleara nce of antigens/ toxins Helmi nths MS Thyroiditis RA IDDM Scler oderma poison ivy Aller gy Autoantibody SLE Immunopathophysiology of Diabetes Immunopathology of MS + T cells and dying, MHC class II Myelin + oligodendrocyte Perivascular infiltrate of + T cells and s Dendritic cell/ DR3, DR4,,DQ8/gad, insulin peptide + (TH2 ) L L + (TH0 ) IL-12 FasL perforin CD8+ CTL L TH1 + T Fc R /dendritic cell IL-1, TNF, LT, NO, PGE-2 Oligodendrocytes naked axon (plaque)?anti-insulin, B GAD ab anti- Mog?Antibody mediated injury β islet cells β cell death 3

4 IL-2R IL-2 + T + T B MHC class II Pathophysiology of Scleroderma α,β SmIg SmIg α,β IL-2,, IL-5, IL-6 Plasma DR/peptide Dermal fibroblast IL-1, TNF, TGF-β Fibroblast proliferation Fibrosis PGE 2, collagen Anti-scl 70, Ro, La and RFs SLE pathogenesis Genetic susceptibility: Complex polygenic Genes Involved: MHC class II Complement deficiency Multiple non-mhc (unknown) X-chromosomal (unknown) Other genetic influences? Environmental triggers (drugs, microbes?) Self-antigen driven + T cell Driving force Autoreactive to self peptides Autoreactive B cells IgG autoantibody Production Autoantibody-mediated Disease Two major mechanisms of antibodymediated tissue injury operating in SLE Serum Sickness develops after injection of soluble foreign antigens Type of antibody induced injury Immune complex formation and deposition Mechanism of injury Ag/Ab complexes deposit in vessel walls, causing inflammation by activation of complement cascade and activation of FcR on phagocytes, mesangial cells, NK cells Clinical consequences glomerulonephritis Dermatitis Serositis (arthritis, pleuritis, pericarditis) Diffuse vasculitis Disease: Vasculitis Glomerulitis Arthritis Pleuritis Pericarditis Dermatitis Direct binding to and lysis of cells Antibody binds to and kills cells by activating the complement attack complex or interacting with FcR ex pressing phagocytes or NK cells Hemolytic anemia Thrombocytopenia Leukopenia Aplastic anemia Why do SLE patients make autoantibodies? Why do SLE patients make autoantibodies? (1) Anti-self immunity: abrogation of self tolerance SLE might be the result of insufficient elimination of autoreactive T cell clones in the thymus or periphery. This might result in such autoreactive T cells being released into the peripheral circulation and causing the autoimmune features of the disease (2) Hidden antigens The nuclear and cytoplasmic antigens that are associated with autoimmunity are not commonly exposed to the immune system. If such antigens (dsdna, for example) are liberated during cellular turnover, they may incite an immune response. Thereafter, further release of such antigens might form the nidus for IC (3) Cross reactivity SLE might be a disease caused by an unknown pathogen such as a virus or a bacterium. The interaction of pathogen derived peptides with a susceptible HLA haplotype may elicit "autoimmune" diseases by activating pathogenic T cells. Such a pathogen has not been identified in SLE, but no feature of the disease suggests that this could not be the etiology. (4) Abnormal regulation: failure of suppression SLE might arise as a consequence of abnormalities in regulatory + or CD8+ T cells. 4

5 Evidence that T cells are important in the development of SLE The pathogenic anti-dna antibodies in SLE are high affinity IgG molecules. Because it is known that class switching to IgG as well as somatic mutation and affinity maturation requires T cells we infer that anti-dna antibody-producing B cells are expanded in SLE by a process that mimics the normal + T cell-dependent responses, involving common mechanisms of somatic mutation, affinity maturation, and IgM to IgG class switching. The MHC class II restriction and the known association of DR2 and DR3 with susceptibility to SLE also strongly point to a predominant role + T cells in the induction of autoimmunity in SLE. Finally, animal models of SLE are effectively treated with molecules which block key functions of + T cells. MHC/self-peptide MHC/Vβ Vβx + Vβx T cell Induction of + TH1 mediated autoimmunity: A paradigm for the pathogenesis of rheumatoid arthritis, multiple sclerosis and type I diabetes Vβx autoreactive + Vβx TH1 cell (1) expansion of +, autoreactive TH1 cells specific for autoantigens (2) migration and infiltration of these self reactive + TH1 cells into tissues and induction of inflammation and autoimmunity (3) induction of regulatory cells and cytokines which control the growth and activation of the pathogenic autoreactive + T cells + TH1 T- Interactions Induce Synovial Proliferation and L DR4/peptide Fc Receptor IL-1, TNF, TGFβ Synovial Proliferation Rheumatoid factor (RF) BONE RESORBTION inflammation Synthesis of PGE-2, Collagenase, IL-1 Dendritic cell/ + (TH2 ) DR4/RA peptide Plasma Immunopathophysiology of Rheumatoid Arthritis Vasculitis + (TH0 ) IL-12 Sm Ig Inflammation RA antigen B Rheumatoid factor (RF) Synovia l fibrobla st (1) Synthesis of PGE-2, Collagenase, IL-1 (2) synovial cell proliferation TH1 + T L RF Fc R IL-1, TNF, TGFβ PGE-2, collagenase chemokines Osteoclast activation Endothelial cell Bone and hypothalamus cartilage destruction Fever Rheumatoid Factors and Immune Complexes Augment the of s + TH1 IL-1 L DR4/peptide Fc Receptor Rheumatoid factor (RF) Rheumatoid factor (RF) or immune complexes Increased synthesis of IL-1, TNF, TGF-β, IL-6, PGE 2 and Collagenase TNF, IL-1 and RANK-L activate osteoclasts to induce bone resorption Soluble RANK Receptor (osteoprotegerin) Precursor Osteoclast + T RANK-L Soluble RANK-L RANK TNF Osteoclast TNFR TNF IL-1 PGE 2 Mφ/dendritic cell MHC class II Bone Resorption 5

6 Mechanisms of action of drugs used to treat RA Spondyloarthritis Diseases (a) Block T- interaction antibodies to MHC class II, or the (b) Decrease T cell activation cyclosporine, anti-cd3, anti-8, anti-cd80 (), anti-l, CTLA-4 agonist (e) Inhibit products of T/macrophages NSAIDs, TNF receptor inhibitors, IL-1 receptor inhibitors (c) Prevent T cell, B cell or synovial cell proliferation Methotrexate, immuran, cytoxan (d) Inhibit T cell or function steroids, gold, penicillamine 2. Genetic:- Susceptibility to develop disease is associated with inheritance of certain MHC class I alleles, notably HLA-B27 3. Pathogenesis:- CD8 T cells are centrally implicated while T cells or B cells are not essential as shown by MHC class I HLA associations, plus: Occur at increased prevalence in those with advanced AIDS No Autoantibodies Seronegative CD8 T cells activated, clonally expanded and sometimes show antigen drive in sites of inflammation Spondylitis Diseases Ankylosing spondylitis Reiter s syndrome / reactive arthritis Psoriatic arthritis Undifferentiated spondyloarthritis Enteropathic arthritis (ulcerative colitis, regional enteritis) Spondyloarthritis Diseases 2. Genetic:- Susceptibility to develop disease is associated with inheritance of certain MHC class I alleles, notably HLA-B27 3. Pathogenesis:- CD8 T cells are centrally implicated while T cells or B cells are not essential as shown by MHC class I HLA associations, plus: Occur at increased prevalence in those with advanced AIDS No Autoantibodies Seronegative CD8 T cells activated, clonally expanded and sometimes show antigen drive in sites of inflammation Spondylitis Diseases Ankylosing spondylitis Reiter s syndrome / reactive arthritis Psoriatic arthritis Undifferentiated spondyloarthritis Enteropathic arthritis (ulcerative colitis, regional enteritis) Reiter s syndrome-reactive arthritis -Mechanism Disruption of tolerance of autoreactive CD8 T cells likely occurs through a combination of mechanisms: Molecular mimicry - Older theory T cell clones involved in attack on microorganisms expand and initiate attack on cells expressing target proteins that contain peptides that mimic the amino acid sequence found in the microorganisms Provision of co-stimulatory signals by activated dendritic cells and macrophages in initial immune response to infection disrupts anergic or unreactive state of T cells CD8 T cells express NK and other receptors that foster the activation of these cells by danger signals recognized by innate immune system receptors 6

7 CD8 T-cell Cognitive Recognition Synovial or Tendon Fibroblast Self Antigenic Peptide MHC class I Molecule Fibroblast Periosteal new bone formation CD8 T-cell and Clonal Expansion Rx Methotrexate Angiogenesis Lining & Infiltrating Monocyte / macrophage Rx TNF-α blockers and CD8 T Recruitment Synoviocyte Proliferation and Alteration in Gene Expression Inflammation, Destruction & Fibrosis 7