1. Introduction to Autoimmunity Alon Monsonego, Ph.D. The department of Microbiology and Immunology Tel: 08-647-9052

2. T-cell selection T-cell activation T-cell regulation Topics:

3. The Development and Survival of Lymphocytes

4. Figure 7-2 part 1 of 2 The development of T cells:

5. Figure 7-2 part 2 of 2

6. Figure 7-8 part 1 of 2 The cellular organization of the human Thymus:

7. Figure 7-9

8. Figure 7-10 The thymus is critical for T-cell maturation:

9. Figure 7-12 Changes in cell surface molecules throughout T-cell maturation in the Thymus:

10. Figure 7-14

11. Figure 7-32 part 1 of 2 Positive selection in the thymus:

12. Figure 7-32 part 2 of 2

13. Figure 7-35 Negative selection in the thymus by bone marrow derived cells:

14. Figure 7-36

15. Figure 13-9 Expression of AIRE in the thymus shape the immune repertoire:

16. Summary: Lymphocytes originate in the bone marrow. B cells mature in the bone marrow T cells mature in the thymus Positive and negative selection mechanisms shape the lymphocyte repertoire

17. T Cell-Mediated Immunity

18. Figure 8-3 dictate Distribution of APCs in the lymph nodes:

19. Figure 8-4 Naïve T cells encounter antigen in the peripheral lymph node:

20. Figure 8-13 Two signals are required to induce T-cell activation:

21. Figure 8-14 DC’s maturation as APCs:

22. Figure 8-15

23. Figure 8-21 T-cell tolerance to antigens expressed on tissue cells:

24. Figure 8-24 Activation of CD4 T cells:

25. Figure 8-31 Effector T cells with different functions:

26. Figure 8-32 part 1 of 3 T-cell cytokines:

27. Figure 8-32 part 2 of 3

28. Figure 8-32 part 3 of 3

29. Molecular differentiation of Th1,Th2, and Th17 T cells

30. Summary: Antigens are processed and presented to T cells by professional APCs (B cells, Mac, and DCs). Two signals are required to induce T-cell activation by APCs. The inflammatory environment shapes the activation of both T cells and APCs The function of T cells (CD4/CD8) differs primarily according to their cytokine profile.

31. Mechanisms of autoimmune diseases

32. Figure 13-1

33. Figure 13-6

34. Figure 13-31

35. Figure 13-3 T-cell mediated paralysis in a mouse model of multiple sclerosis:

36. Figure 13-34

37. Mechanisms of immune regulation Regulatory T cells

38. The principal T cell membrane proteins involved in antigen recognition and in responses to antigens are shown. The functions of these proteins fall into three groups: antigen recognition, signal transduction, and adhesion. Antigen receptors and the immunological synapse:

39. Figure 13-14 By stander suppression

40. CD4+CD25+ cells: About 5-10% of CD4 cells. Generated in the thymus possibly via high affinity interactions with self ligands presented by thymic stromal cells. Extensive proliferation in vivo; depending on the presence of specific Ag. Their development and maintenance is highly dependent on costimulation and IL-2. Express CD25, TNFa receptor, CTLA-4, and Foxp3. MicroRNAs are involved in their differentiation.

41. Mechanism of action: Antigen specificity is unknown but most likely selected and respond to self Ags. Suppression is contact and also cytokine dependent (TGF-b/ IL-10). Act in tissues to control inflammation via direct effects on effector T cells or DCs.

42. Foxp3: Highly enriched in CD4+CD25+ cells. Its expression induces Treg activity. Targeted disruption prevents Treg development and results in autoimmune diseases in mice and humans (IPEX-immune dysregulation, polyendocrinopathy, enteropathy, X-linked). Leads to type-1 diabetes, allergy, and other. Induced by TGF-b in CD4+CD25- cells and lead to expansion of CD4+CD25+ in vitro and in vivo. Foxp3 binds other transcrition factors such as NFAT, AML1, RUNx1.

43. Different subsets of Tregs CD4CD25 10% of CD4

44. A balance between regulation and activation:

47. Figure 13-15 part 1 of 2 CD4CD25 regulatory T cells inhibit colitis:

48. Figure 13-15 part 2 of 2

49. Anti-ergotypic T cells: Teff Treg TCR-Ag CTLA-4-CD80/86 APC Terg TCR-Ag(HSP/CD25) MHC-Ag TCR

51. Tr1 cells: Produce IL-10 already at 4 hr after activation. Express high levels of CTLA-4. CTLA-4 dependent production of TGF-b. Express both Th1 and Th2 chemokine receptors. Proliferate poorly following activation due to autocrine effect of IL-10. IL-15 induces their proliferation as well as high levels of IL-2.

52. Mechanism of action: Suppress T-cell proliferation via rapid secretion of IL-10 and TGF-b. Suppression is reversed by neutralizing ab’s. Suppression of immunoglobulin by B cells. TCR ligation is essential for suppression. Suppression is more efficient with cell contact and may be antigen non-specific.

55. Th3 cells: TGF-b secreting cells in Peyer’s patches 24-48 hrs after low dose feeding of self Ag.

56. (Intraepithelial lymphocyte)

58. Figure 13-16

59. The role of costimulation in T-cell suppression (1) Teff Treg TCR-Ag CTLA-4-CD80/86 APC

60. Teff Treg TCR-Ag CTLA-4-CD80/86 APC IDO Tryptophan IDO-indoleamine 2,3-dioxygenase Costimulation 2.

61. Costimulation 3. Teff TCR-Ag CTLA-4-CD80/86 APC Teff CD80/86- CTLA-4