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

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

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

Antigen-specific unresponsiveness 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

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

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 For T-dependent antigen responses:

T K.L. McCoy

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

Peripheral tolerance mechanism 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

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

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

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

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

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

Review of T Cell Activation Cropped Review of T Cell Activation

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

Other cell types lack MHC class II and co-stimulatory molecules. 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

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

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

Modified

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

Figure 3-30 The Immune System 2nd ed Garland

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

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

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

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

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

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

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

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

Example of Immunological Ignorance

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

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

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

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

T K.L. McCoy