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Download 11. Tolerance induction and regulation of autoimmunity (Alon
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Introduction to Autoimmunity Alon Monsonego, Ph.D. The department of Microbiology and Immunology Tel: 08-647-9052 Topics: • T-cell selection • T-cell activation • T-cell regulation The Development and Survival of Lymphocytes The development of T cells: Figure 7-2 part 1 of 2 Figure 7-2 part 2 of 2 The cellular organization of the human Thymus: Figure 7-8 part 1 of 2 Figure 7-9 The thymus is critical for T-cell maturation: Figure 7-10 Changes in cell surface molecules throughout T-cell maturation in the Thymus: Figure 7-12 Figure 7-14 Positive selection in the thymus: Figure 7-32 part 1 of 2 Figure 7-32 part 2 of 2 Negative selection in the thymus by bone marrow derived cells: Figure 7-35 Figure 7-36 Expression of AIRE in the thymus shape the immune repertoire: Figure 13-9 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 T Cell-Mediated Immunity Distribution of APCs in the lymph nodes: Figure 8-3 dictate Naïve T cells encounter antigen in the peripheral lymph node: Figure 8-4 Two signals are required to induce T-cell activation: Figure 8-13 DC’s maturation as APCs: Figure 8-14 Figure 8-15 T-cell tolerance to antigens expressed on tissue cells: Figure 8-21 Activation of CD4 T cells: Figure 8-24 Effector T cells with different functions: Figure 8-31 T-cell cytokines: Figure 8-32 part 1 of 3 Figure 8-32 part 2 of 3 Figure 8-32 part 3 of 3 Molecular differentiation of Th1,Th2, and Th17 T cells 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. Mechanisms of autoimmune diseases Figure 13-1 Figure 13-6 Figure 13-31 T-cell mediated paralysis in a mouse model of multiple sclerosis: Figure 13-3 Figure 13-34 Mechanisms of immune regulation Regulatory T cells Antigen receptors and the immunological synapse: 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. Figure 13-14 By stander suppression 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. 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. 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. Different subsets of Tregs CD4CD25 10% of CD4 A balance between regulation and activation: CD4CD25 regulatory T cells inhibit colitis: Figure 13-15 part 1 of 2 Figure 13-15 part 2 of 2 Anti-ergotypic T cells: CTLA-4-CD80/86 Treg TCR-Ag Teff APC TCR-Ag MHC-Ag TCR TCR-Ag(HSP/CD25) Terg 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. 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. Th3 cells: • TGF-b secreting cells in Peyer’s patches 24-48 hrs after low dose feeding of self Ag. (Intraepithelial lymphocyte) Figure 13-16 The role of costimulation in T-cell suppression (1) CTLA-4-CD80/86 Treg TCR-Ag Teff APC TCR-Ag Costimulation 2. Treg CTLA-4-CD80/86 TCR-Ag Teff APC IDO IDO-indoleamine 2,3-dioxygenase TCR-Ag Tryptophan Costimulation 3. CTLA-4-CD80/86 Teff TCR-Ag CD80/86- CTLA-4 APC Teff TCR-Ag