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T cell &

T cell &. T cell-mediated immunity. Rui He ruihe@fudan.edu.cn Department of Immunology Shanghai Medical School Fudan University. Types of adaptive immune responses. Agenda. Types of cell-mediated immune reactions The differentiation of CD4+Th cell subsets

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T cell &

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  1. T cell & T cell-mediated immunity Rui He ruihe@fudan.edu.cn Department of Immunology Shanghai Medical School Fudan University

  2. Types of adaptive immune responses

  3. Agenda • Types of cell-mediated immune reactions • The differentiation of CD4+Th cell subsets • Effector mechanisms of cell-mediated immunity

  4. Types of cell-mediated immune reactions • CD4+ Th responses • CD8+ CTL responses Delayed-type Hypersensitivity (DTH) T cell-dependent immune reactions that cause normal tissues injury NK cell mediated innate immunity, kill infected cell early

  5. Different types of microbes elicit distinct protective T cell responses • CD4+ Th1 responses microbes residing within the phagosomes of phagocytes • CD8+ CTL responses microbes residing in the cytoplasm of various cell types • CD4+ Th2 responses • helminthic parasites Defects in CMI result in increased susceptibility to infection by viruses and intracellular bacteria

  6. Cell-mediated immune responses • The development of effector T cells • Migration of effector T cells and other leukocytes to sites of infection • Effector functions to eliminate microbes

  7. The differentiation of CD4+Th cell subsets

  8. The subsets of CD4+Th cells • How they are induced, • What cytokines they produce • What effector mechanisms they activate

  9. Properties of CD4+ Th1 and Th2 subsets

  10. Differentiation of Th1 Subset • Stimulated by intracellular microbes that infect or activate macrophages or NK cells • Listeria, mycobacteria and Leishmania • Important cytokines for the Th1 differentiation • IL-12 • IFN- • IL-18 • type I IFNs (in human) • Important transcription factors (TF) for the Th1 differentiation • T-bet: master regulator • STAT4 • STAT1

  11. The molecular basis of Th1 differentiation The interplay of signals from the T cell receptor, the cytokines IFN- and IL-12, and the TF T-bet, STAT1, and STAT4 IL-12 STAT-4 IFN- STAT-1 Ag recognition by TCR T-bet A positive amplification loop between T-bet and IFN-

  12. Differentiation of Th1 subsets

  13. Differentiation of Th2 Subset • Stimulated by microbes and antigens that cause persistent or repeated T cell stimulation with little inflammation or macrophage activation Helminth and allergens • Important cytokines for the Th1 differentiation • IL-4 • Important TF for the Th2 differentiation • GATA-3: master regulator • STAT6

  14. Th2 differentiation is dependent on IL-4 IL-4 STAT-6 Ag recognition by TCR GATA-3 The molecular basis of Th2 differentiation The interplay of signals from the T cell receptor, the cytokine IL-4, and the TF GATA-3 and STAT6

  15. GATA-3 A master regulator of Th2 differentiation • Enhances expression of the Th2 cytokine genes IL-4, IL-5, and IL-13 by 1) directly interacting with the promoters of these genes 2) causing chromatin remodeling • Enhances its own expression via a positive feedback loop • Blocks Th1 differentiation

  16. Development of Th2 subsets

  17. Development of Th1 and Th2 subsets

  18. Stimuli that influence the pattern of Th cell differentiation • Cytokines • High doses of antigen without adjuvants • Different subsets of dendritic cells may exist • The genetic makeup of the host

  19. Th1-Mediated Immune Responses • The physiological role of Th1 cells phagocyte-mediated defense against infections, especially with intracellular microbes • Pathological roles of Th1 cell Many organ-specific autoimmune diseases and inflammatory reactions are due to excessive activation of Th1 cells

  20. Effector functions of Th1 cells

  21. IFN- • The major sources: Th1, CD8+ T cells • The major macrophage-activating cytokine • Stimulates the microbicidal activities of phagocytes • Stimulates the production of IgG Abs to promote the phagocytosis of microbes

  22. T cell signals that activate macrophages • IFN- • CD40L-CD40 interactions

  23. CD40L/CD40 Deliever contact-mediated signals activates the transcription factors nuclear factor κB (NF-κB) and activation protein-1 (AP-1) Clinical evidence Humans with inherited mutations in CD40L (X-linked hyper-IgM syndrome) : severe deficiencies in CMI to intracellular microbes

  24. The effector functions of activated macrophages • Killing of phagocytosed microbes • Stimulation of acute inflammation • Tissue Repair • Become the more efficient APCs

  25. Activation and functions of macrophages in CMI

  26. The development of Chronic DTH reactions When a Th1 response to an infection activates macrophages but fails to eradicate phagocytosed microbes. • Fibrosis is a hallmark of chronic DTH reactions • The mechanism of tissue damage in several autoimmune diseases

  27. Th2-Mediated Immune Responses • The physiological role of Th2 cells Elimination of helminthic infection • Pathological roles of Th2 cell The underlying cause of allergic reactions

  28. Effector functions of Th2 cells • Promotion of antigen-specific IgE production • Activation of eosinophils and mast cells • Alternative macrophage activation • Barrier immunity by Th2 cytokine

  29. Effector functions of Th2 cells

  30. The effector function of Th2 cytokines • IL-4 and IL-13 • Stimulate the production of antigen-specific IgE • Alternatively activate macrophages • IL-4 promotes expulsion of microbes while IL-13 stimulates mucus • secretion • IL-5 • Recruit and activate eosinophils

  31. The Th17 Subset

  32. Th17-Mediated Immune Responses • The physiological role of Th17 cells Protection against extracellular bacterial and fungal infections • Pathological roles of Th17 cell may be important in meditating tissue damage in immune-mediated inflammatory diseases, e.g. autoimmune diseases

  33. Cytotoxic T Lymphocytes (CTLs) Effector CD8+ T Cells Eliminate intracellular microbes mainly by killing infected cells

  34. CTL-mediated cytotoxcity • Antigen specific Only kill targets that express the same class I-associated antigen that triggered their differentiation from naïve CD8+ T cell • Contact dependent The formation of immunological synapse the specific delivery of the molecules

  35. Immune synapse between CTLs and a target cell

  36. Steps in CTL-mediated lysis of target cells • antigen recognition, • activation of the CTLs, • delivery of the "lethal hit" that kills the target cells, • release of the CTLs from target cell

  37. Steps in CTL-mediated lysis of target cells

  38. Recognition of Antigen and Activation of CTLs

  39. Recognition of Antigen and Activation of CTLs

  40. Mechanisms of CTL-mediated lysis of target cells • Fas/FasL pathway • Granule exocytosis

  41. The two important granule proteins for CTL killing function • Perforin • a pore-forming protein molecule • Main function is to facilitate delivery of the granzymes into the cytosol of the target cell • Granzymes (granule enzymes) • Serine proteases, including A. B.C • Granzymes B initiate apoptotic pathways involve caspases.

  42. Mechanisms of CTL-mediated lysis of target cells

  43. Release of CTL from its target cell • Usually occurs even before the target cell goes on to die • May facilitated by decreased affinity of accessory molecules for their ligands

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