* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Immune Regulation, Tolerance, and Autoimmunity
Survey
Document related concepts
DNA vaccination wikipedia , lookup
Immune system wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Adaptive immune system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Autoimmunity wikipedia , lookup
Innate immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Transcript
1 Immune Regulation, Tolerance, and Autoimmunity Mark S. Anderson, MD, PhD UCSF 2 Disclosures • Research support from Juno Therapeutics • Consultant for Sanofi 3 Lecture outline • Principles of immune regulation • Self-tolerance; mechanisms of central and peripheral tolerance • Inhibitory receptors of T cells • Treg’s and IL-2 The immunological equilibrium: balancing lymphocyte activation and control Activation Effector T cells Normal: reactions against pathogens Inflammatory disease, e.g. reactions against self Tolerance Regulatory T cells Controlled response to pathogens No response to self 3 Central and peripheral tolerance to self The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT: Some B cells may change their specificity (called “receptor editing”) Some T cells may differentiate into regulatory (suppressor) T lymphocytes Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier 5 Consequences of self antigen recognition in thymus Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier 6 7 What self antigens are seen in the thymus? • Ubiquitous cell-associated and circulating proteins • The thymus has a special mechanism for displaying peripheral tissue antigens in thymic medullary epithelial cells, where they signal self-reactive thymocytes for death Consequences of AIRE mutation • Human disease: autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1) – Associated gene identified by positional cloning, named AIRE (“autoimmune regulator”) • Mouse knockout: autoantibodies against multiple endocrine organs, retina – Failure to express many self antigens in the thymus --> failure of negative selection 8 Deletion of self-reactive T cells in the thymus: 9 how are self antigens expressed in the thymus? Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014 AIRE (autoimmune regulator) is a regulator of gene transcription that stimulates thymic expression of many self antigens which are largely restricted to peripheral tissues NOD.Aire GW/+ mice develop peripheral neuropathy (CIDP) Sciatic Nerve Peripheral T cell tolerance Abbas, Lichtman and Pillai. Basic Immunology, 4th edition, 2014 11 12 T cell anergy Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier 13 CTLA-4 competitively inhibits B7-CD28 engagement APC APC B7 CD28 T Cell B7 CTLA-4 T cell (activated T cell or Treg) Costimulation T cell activation CTLA-4 blocks and removes B7 lack of costimulation T cell inhibition The B7:CD28 families Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014 14 Activation • CD28-B7: initiation of immune responses • ICOS-ICOS-L: T cell help in germinal center reactions (antibody responses) Inhibition Major functions of selected B7-CD28 family members • CTLA-4-B7: inhibits early T cell responses in lymphoid organs • PD-1:PD-L1,2: inhibits effector T cell responses in peripheral tissues 15 Blocking CTLA-4 promotes tumor rejection: CTLA-4 limits immune responses to tumors Administration of antibody that blocks CTLA-4 in tumor-bearing mouse leads to tumor regression 16 17 The PD-1 inhibitory pathway • PD-1 recognizes two widely expressed ligands (PD-L1, PD-L2) • Knockout of PD-1 leads to autoimmune disease (less severe than CTLA-4-KO) • Role of PD-1 in T cell suppression in chronic infections, tumors? 18 T cell “exhaustion” in chronic viral infections Naïve CD8+ T cells Virus Effector T cells Acute infection: clearance of virus Memory T cells: enhanced antiviral responses Chronic infection: persistence of virus Exhausted T cells: inability to respond to virus (expression of inhibitory receptors, e.g. CTLA-4, PD-1) 19 Actions of PD-1 • PD-1 attenuates TCR signaling in responding T cells • Limits harmful consequences of chronic stimulation with persistent antigen (self, tumors, chronic viral infections) • Greater role in CD8 than in CD4 T cells • Also expressed on follicular helper T cells; function? Checkpoint blockade for cancer immunotherapy e.g. ipilimumab Ribas A. N Engl J Med 2012;366:2517-2519. Checkpoint blockade for cancer immunotherapy e.g. ipilimumab Ribas A. N Engl J Med 2012;366:2517-2519. 21 e.g. nivolumab, pembrolizumab 22 Risks of blocking CTLA-4 or PD-1 • Blocking a mechanism of self-tolerance leads to: 23 Risks of blocking CTLA-4 or PD-1 • Blocking a mechanism of self-tolerance leads to: • Autoimmune reactions (a new cottage industry for clinicians?) – Colitis and dermatitis are common – Vitiligo, Endocrinopathies, hepatitis less common but described – Severity of adverse effects has to be balanced against potential for treating serious cancers – Less severe with anti-PD1 antibody Regulatory T cells Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014, Elsevier 24 25 Properties of regulatory T cells • Phenotype: CD4+, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markers • Essential features of stable Tregs: – Foxp3 expression: requires demethylated noncoding CNS2 sequence in promoter – CD25 (IL-2Ra) expression: IL-2 is a necessary survival factor – CTLA-4 expression: required for suppressive function of most Tregs – (Inability to produce IL-2) Take home messages 26 The significance of Foxp3+ Tregs • Genetic evidence: Foxp3 mutations --> autoimmune disease (IPEX); in mice, disease can be corrected by providing normal Foxp3+ cells • Do defects in Foxp3+ Tregs or resistance to Treg-mediated suppression contribute to common autoimmune diseases? – Inconsistent and variable data Mechanisms of action of Foxp3+ Tregs • CTLA-4 on Tregs removes B7 on APCs, reduces CD28 engagement and T cell activation – Genetic deletion of CTLA-4 in Foxp3+ cells results in severe systemic autoimmunity and lymphoproliferation • Inhibitory cytokines produced by Tregs (TGF-b, IL-10, others?) suppress immune responses (DCs, Macs, T cells) – IL-10 deletion in Foxp3+ cells results in colitis – IL-10 is also produced by Foxp3- cells • Consumption of IL-2 27 28 Regulatory T cells • Explosion of information about the generation, properties, functions and significance of these cells • Will cellular therapy with ex vivo expanded Treg become a reality? • Therapeutic goal: induction or activation of Treg in immune diseases Take home messages The therapeutic potential of regulatory T lymphocytes • Cell transfer of autologous Tregs to suppress immune responses – Grow up patient’s Tregs ex vivo – Ongoing clinical trials in graft rejection, T1D show it is safe – In one study of liver Tx, single infusion of Tregs resulted in tolerance (withdrawal of immunosuppression) in 7/10 patients (vs ~10% historically) 29 Functions of Interleukin-2: the dogma 30 31 The unexpected biology of IL-2 • Interleukin-2 is the prototypic T cell growth factor (TCGF), required for initiating clonal expansion of T cells in response to antigen • BUT: knockout of IL-2 or the a or b chain of the IL-2R results not in immune deficiency but in systemic autoimmunity and lymphoproliferation Dual roles of IL-2 in T cell responses 32 Surprising conclusion from knockout mice: the non-redundant function of IL-2 is in controlling immune responses Take home messages due to IL-2R signalli 33 PI3K–AKT and STA effector T cells in re and IL-2, TReg cells — levels inhibit the P way 43,44 — may be signalling (FIG. 2). In vivo experime ings. At doses of IL- Differential effects of IL-2 on Teff vs Treg mTOR mTOR Response ctor Reg c ll 100 80 60 40 20 0 0.01 0.1 1 10 100 80 60 20 0 0.01 0.1 IL-2 IU ml–1 Fold increase in the number of cells over baseline Fold increase in the number of cells over baseline 1 0 Baseline 5 days of low-dose IL-2 1 10 100 1,000 IL-2 IUml–1 In vivo sensitivity to IL-2 2 IL-2 international units are expanded compa and they express hig are more suppressiv clonal expansion nor T cells or of NK cells 40 100 1,000 3 TReg cells E ector T cells In vitro sensitivity to IL-2 STAT5 phosphorylation (%) STAT5 phosphorylation (%) b c ll Response 3 2 1 0 Baseline 5 days of low-dose IL-2 IL‑2 in pat hophysi The inflammatory d ing IL-2 or function and the production but the specific eff mouse strain. On th nant phenotype is a caused by erythrocy C57BL/6 mice, the d time, all Il2-knockou bodies that are spec self-antigens. Intere duced even in germ the colitis is largely mice are made germ 34 Pathogenesis of autoimmunity 35 Therapy of immune disorders: rational approaches target 36 lymphocyte activation and subsequent inflammation Autoimmune diseases • Experimental models are revealing pathways of immune regulation • But experimental animals are often inadequate models of human diseases • Improving technologies for human genetic and phenotypic analyses are enabling studies of patients • Challenges: – Defining which mechanisms of immune tolerance fail in different autoimmune diseases – Using this knowledge to develop therapies Take home messages 37 The landscape of T cell activating and inhibitory receptors: More to come? TIGIT 38