Mechanisms of T Cell Tolerance

1. Mechanisms of T Cell Tolerance Kathleen L. McCoy, Ph.D. kmccoy@vcu.edu

2. BACKGROUND • Inherent nature of immune system is to respond to antigens • Immune tolerance is the lack of response to self antigens or innocuous non-self antigens • Protects against “over reactions” that can cause death • Is NOT immunodeficiency leading to infections

3. GENERAL CONCEPTS • Immune system distinguishes between self (auto) and non-self (foreign) antigens • V genes encode TCR’s and BCR’s with anti-self reactivity • Autoreactive T and B cells are produced • If autoreactive T and B cells mature and are activated, autoimmune disease may develop • Self-tolerance mechanisms eliminate or prevent autoreactive cells from responding

4. IMMUNE TOLERANCE • Antigen-specific unresponsiveness • Acquired characteristic - Not inherent • Results from somatic processes • Induced by multiple mechanisms • Tolerance mechanisms can be manipulated • Basis for immunotherapy

5. IMMUNE TOLERANCE • Central tolerance occurs in primary lymphoid organs during lymphocyte maturation • Peripheral tolerance occurs in secondary lymphoid organs involving mature cells • Time dependent Easiest to tolerize immature lymphocytes Very difficult to tolerize memory cells • Antigen concentration dependent Low vs. High Zone Tolerance

6. For T-dependent antigen responses: T cells are easier to tolerize than B cells. If helper T cell is tolerant, B cell will not respond. Without cytokines from helper T cell, B cell undergoes apoptosis. Cropped Figure 7-12 The Immune System 2nd ed Garland

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8. Mechanisms of T Cell Tolerance • Deletion • Immune Privileged Sites - Antigen Sequestration • Anergy • Suppression • Immunological Ignorance • Receptor Editing - NOT Important

9. DELETION • Autoreactive cells killed • Negative selection in thymus Main mechanism of central tolerance • Activation-induced cell death Peripheral tolerance mechanism T cells die during an immune response

10. Selection in the Thymus Figure 5-13 The Immune System 2nd ed Garland

11. Impact of Thymic Selection Modified Fig. 13.30 Immunobiology 4th ed. Janeway et al. Garland

12. Activation-Induced Cell Death Fas binds Fas ligand. Apoptosis is mediated by Fas pathway. Defects in Fas pathway lead to severe systemic autoimmune diseases Modified Fig. 10.36 Immunobiology 6th ed. Janeway et al. Garland

13. Fetus inherits MHC genes from father, which are co- dominantly expressed, and is allogeneic to mother. Fetus is an allograft, but no immune response occurs. Figure 12-15 The Immune System 2nd ed Garland

14. Immune Privileged Sites • Lack of immune response to allografts • Examples: fetus, brain, anterior chamber of eye • Lymphocytes have access and self antigens exit • Lack of conventional lymphatic vessels • Rich in inhibitory molecules

15. Review of T Cell Activation Cropped

16. ANERGY • Peripheral tolerance mechanism • Cells remain alive • Cells functionally inactivated • Not capable of responding to antigen • Long-lasting effect - Not permanent • Caused by improper primary signal or lack of co-stimulatory signal

17. Naive T cells interact with professional antigen-presenting cells for a primary response. Other cell types lack MHC class II and co-stimulatory molecules. CD8+ Modified

18. Cropped Figure 6-19 Part 1 of 2 The Immune System 2nd ed Garland

20. Lack of signal via CD28 renders T cells unable to produce IL-2

21. Modified

22. Fig. 8.12 Immunobiology 6th ed. Janeway et al. Garland Particular CTLA-4 allele increases risk to develop certain autoimmune diseases

23. Figure 3-30 The Immune System 2nd ed Garland

24. Analog Peptides = Peptide Agonists Peptide agonists act as partial agonists and cause a negative signal to T cells Fig. 12.10 Immunobiology 1st ed. Janeway et al. Garland

25. Role of CD4 and CD8 co-receptors in TCR primary signal Cropped Figure 6-16 The Immune System 2nd ed Garland

26. Disruption of co-receptor function during primary responses causes tolerance Fig. 14.6 Immunobiology 6th ed. Janeway et al. Garland

27. SUPPRESSION • Unique Hallmark Feature: Adoptively transferred with T cells • Infectious tolerance • Regulatory CD4+ CD25+ T cells secrete inhibitory cytokines • Release of soluble cytokine receptors • Immune Deviation (Cytokine Deviation) - Change Th1 to Th2 response or reverse

28. Major Form of Suppression Modified Mutations in FoxP3 cause fatal multi-organ autoimmune disease called IPEX

29. Soluble cytokine receptors neutralize cytokines Modified Fig. 9.24 Immunobiology 6th ed. Janeway et al. Garland

30. Immune Deviation - Cytokine Deviation Change in Cytokines Produced = Profile Subverts main pathological mechanism causing tissue destruction Cropped Figure 6-26 The Immune System 2nd ed Garland

31. IMMUNOLOGICAL IGNORANCE • Peripheral tolerance mechanism • Cells are alive and capable of responding • Cells are “ignorant” of antigen and do not respond • Occurs if TCR has low affinity and/or antigen concentration is low • Increase in antigen concentration may lead to a response

32. Example of Immunological Ignorance

33. Promising Immunotherapies - To Induce Anergy • Soluble CTLA-4 to treat autoimmune diseases and prevent graft rejection Orencia is FDA-approved for rheumatoid arthritis • Anti-B7 antibodies to prevent graft rejection • Peptide agonists to treat allergies • Anti-CD4 antibody to prevent graft rejection and treat multiple sclerosis

34. Promising Immunotherapies -To Induce Suppression • Soluble TNF receptor to treat rheumatoid arthritis, ankylosing spondylitis and severe psoriasis Enbrel is FDA-approved • Th1 cytokines to treat IgE-mediated allergies

35. Promising Immunotherapies for Cancer -To Break Self Tolerance • Killed tumor cells expressing B7 genes to induce T cell responses • Tumor cells as antigen-presenting cells • Clinical trials with melanoma, renal cell carcinoma, and glioblastoma patients

36. Promising Immunotherapies for Cancer • Anti-CTLA-4 antibody to boost T cell responses • Impedes anergy & impairs regulatory T cell function • Ipilimumab: FDA application pending to treat melanoma, prostate, & lung cancer • Clinical trials with non-Hodgkin’s lymphoma, colon & ovarian cancer patients

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