1 Immune Regulation, Tolerance, and Autoimmunity Mark S.

1 Immune Regulation, Tolerance, and Autoimmunity Mark S.

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 Tregs 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, 2011c Elsevier

5 6 Consequences of self antigen recognition in thymus Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011c Elsevier 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 8 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 9 Deletion of self-reactive T cells in the thymus 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 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, 2011c Elsevier 13 LA-4 competitively inhibits B7-CD28 engageme 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 B7CD28 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 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 Nave CD8+ T cells Virus Effector T cells Memory T cells: enhance

d antiviral Acute infection: clearance of virus respons es Chronic infection: persistence of virus Exhausted T cells: inability to respond to virus (expression of inhibitory receptors, e.g. CTLA-4, PD- 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 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 selftolerance leads to: 23 Risks of blocking CTLA-4 or PD-1 Blocking a mechanism of selftolerance 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 non-coding 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 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 patients 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 32 Dual roles of IL-2 in T cell responses

urprising conclusion from knockout mice: the non-redundant nction of IL-2 is in controlling immune responses Take home messages mTOR mTOR dueto IL-2R signalli 33 PI3KAKT and STA effector T cells in re and IL-2, TReg cells levels inhibit the P way43,44 may be

signalling (FIG. 2). In vivo experime ings. At doses of IL- Differential effects of IL-2 on Teff vs Treg Response 100 In vitro sensitivity to IL-2 80 60 40

20 0 0.01 3 0.1 1 10 IL-2 IU ml1 80

60 0 Baseline 5 days of low-dose IL-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 20 In vivo sensitivity to IL-2 1 TReg cells 100 100 1,000

2 ll E ector T cells Fold increase in the number of cells over baseline Fold increase in the number of cells over baseline STAT5 phosphorylation (%) b

Reg c STAT5 phosphorylation (%) ctor c ll Response 0 0.01 0.1 1

10 IL-2 IUml1 100 1,000 3 2 1 0

Baseline 5 days of low-dose IL-2 IL2 in pathophysi 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, thed 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 lymphocyte activation and subsequent inflammation

36 37 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 The landscape of T cell activating and inhibitory receptors: More to come? TIGIT 38

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