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

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Presentation on theme: "Introduction to Autoimmunity Alon Monsonego, Ph.D. The department of Microbiology and Immunology Tel: 08-647-9052."— Presentation transcript:

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

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