1 Immune Regulation Tolerance and Autoimmunity Mark S






































- Slides: 38

1 Immune Regulation, Tolerance, and Autoimmunity Mark S. Anderson, MD, Ph. D 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, 7 th edition, 2011 c Elsevier 5

Consequences of self antigen recognition in thymus Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7 th 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, 8 th 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, 4 th edition, 2014 11

12 T cell anergy Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7 th edition, 2011 c Elsevier

13 CTLA-4 competitively inhibits B 7 -CD 28 engagement APC B 7 CD 28 T Cell B 7 CTLA-4 T cell (activated T cell or Treg) Costimulation T cell activation CTLA-4 blocks and removes B 7 lack of costimulation T cell inhibition

The B 7: CD 28 families Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8 th edition, 2014 14

Activation • CD 28 -B 7: initiation of immune responses • ICOS-L: T cell help in germinal center reactions (antibody responses) Inhibition Major functions of selected B 7 -CD 28 family members • CTLA-4 -B 7: inhibits early T cell responses in lymphoid organs • PD-1: PD-L 1, 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-L 1, PD-L 2) • 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 CD 8+ 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 CD 8 than in CD 4 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-PD 1 antibody

Regulatory T cells Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8 th edition, 2014, Elsevier 24

25 Properties of regulatory T cells • Phenotype: CD 4+, high IL-2 receptor (CD 25), low IL-7 receptor, Foxp 3 transcription factor; other markers • Essential features of stable Tregs: – Foxp 3 expression: requires demethylated noncoding CNS 2 sequence in promoter – CD 25 (IL-2 Ra) 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 Foxp 3+ Tregs • Genetic evidence: Foxp 3 mutations --> autoimmune disease (IPEX); in mice, disease can be corrected by providing normal Foxp 3+ cells • Do defects in Foxp 3+ Tregs or resistance to Treg-mediated suppression contribute to common autoimmune diseases? – Inconsistent and variable data

Mechanisms of action of Foxp 3+ Tregs • CTLA-4 on Tregs removes B 7 on APCs, reduces CD 28 engagement and T cell activation – Genetic deletion of CTLA-4 in Foxp 3+ 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 Foxp 3+ cells results in colitis – IL-10 is also produced by Foxp 3 - 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, T 1 D 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-2 R 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

Differential effects of IL-2 on Teff vs Treg 33

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
Primary immune response and secondary immune response
Autoimmunity literally means
Unilateral tolerance and bilateral tolerance
Cellular and molecular immunology
Chapter 24 the immune and lymphatic systems and cancer
Chapter 24 the immune and lymphatic systems and cancer
Chapter 35 immune system and disease
1st 2nd and 3rd line of defense immune system
Lesson 12 blood and immune system
Lesson 12 blood and immune system
Primary and secondary immune response
Peyer's patches
What is the third line of defense in the immune system
Hangman flowchart
Third line of defense immune system
Hydrops fetalis
Primary vs secondary immune response
1st line of defense immune system
Chapter 55 care of the patient with an immune disorder
Ap bio immune system
Cancer vaccines
Immune reconstitution inflammatory syndrome
Predeksihkhariini
Immune system lymph nodes
Immune system definition
Immune complex glomerulonephritis
Overreactions of the immune system
Lymphatic vs immune system
Immune effector cells
Lymphatic vs immune system
Defination of tuberculosis
Primary immune response
Immune effector cells
Immune response controller crossword
Hepatite auto immune fmc
Immune defintion
What are the immune systems 3 lines of defense
Immune
What is the main function of the immune system