Chapter 10 Immunologic Tolerance

1. Chapter 10Immunologic Tolerance • General Features and Mechanisms • T Lymphocyte Tolerance • B Lymphocyte Tolerance • Tolerance induced by Foreign Protein Antigens • Homeostasis in the Immune System

2. What is Immunologic Tolerance? Immunologic Tolerance—— an antigen induced specific unresponsiveness Tolerogens Immunogens Self-tolerance  Autoimmunity Tolerance induced by foreign antigens Failure

3. General Features and Mechanisms • Immunologically specific • A result of antigen recognition by specific lymphocytes

4. Studies of graft rejection in inbred mice Strain A Strain A Strain A Neonate Adult _ Skin graft rejection + + During lymphocyte maturation in the generative lymphoid organs, all lymphocytes pass through a stage in which encounter with Ag leads to tolerance • Immunologically specific • a result of the recognition of antigens by specific lymphocytes

5. General Features and Mechanisms • Immunologically specific • Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

6. Burnet: Clonal selection hypothesis

7. General Features and Mechanisms • Immunologically specific • Central tolerance: generative lymphoid organs immature self-reactive lymphocyte • Peripheral tolerance: peripheral sites mature self-reactive lymphocytes The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens Important for maitaining unresponsiveness to self antigens that are not expressed in the generative lymphoid organs.

8. Peripheral tolerance is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.

9. The principal mechanisms of lymphocyte tolerance • Deletion: apoptotic cell death • Anergy: functional inactivation without cell death • Treg Central tolerance Peripheral tolerance

10. Apoptosis

11. Immunologic Tolerance • General Features and Mechanisms • T Lymphocyte Tolerance • B Lymphocyte Tolerance • Tolerance induced by Foreign Protein Antigens • Homeostasis in the Immune System

12. T Lymphocyte Tolerance • Central T Cell Tolerance • Peripheral T cell Tolerance

13. Maturation of T cells in the thymus

14. High affinity High concentration Negative selection: Development of central tolerance

15. Self antigens expressed in the thymus • ubiquitous self-antigen: widely expressed in the body • tissue-specific antigenautoimmune regulator gene, AIRE

16. Natural Tregs arise in the thymus

18. T Lymphocyte Tolerance • Central T Cell Tolerance • Peripheral T cell Tolerance

19. Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • Activation induced cell death (AICD) • Regulatory T Lymphocytes • Factors that determine the tolerogenicity of self antigens

20. Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Treg • Factors that determine the tolerogenicity of self antigens

21. Two Signal model Sig2 (co-stimulation) 1975 Lafferty & Cunningham T helper cells die when they see antigen unless rescued by co-stimulation(signal two) from APCs.

22. co-stimulatory signal

23. Figure 8-20 Gowth factor: IL-2

24. Anergy is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.

25. Figure 8-12 CTLA-4/B7 initiate the inhibitory signal

26. Anergy may be induced if T cells use CTLA-4 to recognize costimulators on APCs

27. ? ? ? ? ? ? ? Question Factors T cells T cells T cells recognize B7 molecules with CD28 (active receptor) ? Recognize the same B7 with CTLA-4 (inhibitory receptor) Immune response Tolerance

28. Making and breaking tolerance The nature of tissue APCs is an important determinant of whether self-tolerance or autoimmunity develops.

29. Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Treg • Factors that determine the tolerogenicity of self antigens

30. Activation induced cell death Repeated stimulation of T cells by persistent antigen results in death of the activated cells by a process of apoptosis

31. Fas-mediated activation-induced cell death AICD is a form of apoptosis induced by signals from membrane death receptors

32. activation activation The net effect is that the population of mature lymphocytes is depleted of antigen specific lymphocytes by repeated stimulation.

33. Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Regulatory T Lymphocytes (Treg) • Factors that determine the tolerogenicity of self antigens

34. Treg cell development Immunity 2009; 30: p626

35. T cell-mediated suppression

36. Mechanisms of action of regulatory T cells

37. Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Regulatory T Lymphocytes (Treg) • Factors that determine the tolerogenicity of self antigens

38. Factors That Determine the Immunogenicity and Tolerogenicity of Protein

39. Immunologic Tolerance • General Features and Mechanisms • T Lymphocyte Tolerance • B Lymphocyte Tolerance • Tolerance induced by Foreign Protein Antigens • Homeostasis in the Immune System

40. B Lymphocyte Tolerance • Central B Cell Tolerance • Peripheral B cell Tolerance Checkpoints during B cell maturation and activation at which encounter self Ags may abort these process

41. B cell development in bone marrow

43. Central tolerance in B cells • Immature B cells that recognize self antigens in the bone marrow with high affinity are deleted or change their specificity. • multivalent self antigens: cell membrane molecules、polymeric molecules

45. HEL transgenic What is the result of self antigen recognition in generative lymphoid organ? • Down-regulation of antigen receptor expression • Change in receptor specificity (receptor editing)

46. B Lymphocyte Tolerance • Central B Cell Tolerance • Peripheral B cell Tolerance

48. CD28 B7 T-B Collaboration

50. Peripheral tolerance in B cells • Mature B cells that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive. If anergic B cells do encounter any antigen-specific helper T cells, what happened? The B cells maybe killed by FasL on the T cells engaging Fas on the B cells.