1. Mechanisms of T Cell Tolerance
Kathleen L. McCoy, Ph.D.

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. 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

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
For T-dependent
antigen responses:

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K.L. McCoy

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

9. 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

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

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

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

13. Fetus inherits MHC genes from father, which are co-
Figure 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.

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
Review of T Cell Activation

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. 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

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
Analog Peptides =
Peptide Agonists
Fig 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 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
Major Form of
Suppression

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

30. 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

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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K.L. McCoy