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T cell & T cell-mediated immunity Rui He [email protected] 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 Effector mechanisms of cell-mediated immunity 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 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 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 The differentiation of CD4+Th cell subsets The subsets of CD4+Th cells How they are induced, What cytokines they produce What effector mechanisms they activate Properties of CD4+ Th1 and Th2 subsets 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 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- Ag recognition by TCR STAT-1 T-bet A positive amplification loop between T-bet and IFN- Differentiation of Th1 subsets 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 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 Th2 differentiation is dependent on IL-4 IL-4 Ag recognition by TCR STAT-6 GATA-3 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 Development of Th2 subsets Development of Th1 and Th2 subsets 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 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 Effector functions of Th1 cells 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 T cell signals that activate macrophages IFN- CD40L-CD40 interactions 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 The effector functions of activated macrophages Killing of phagocytosed microbes Stimulation of acute inflammation Tissue Repair Become the more efficient APCs Activation and functions of macrophages in CMI 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 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 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 Effector functions of Th2 cells 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 The Th17 Subset 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 Cytotoxic T Lymphocytes (CTLs) Effector CD8+ T Cells Eliminate intracellular microbes mainly by killing infected cells 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 Immune synapse between CTLs and a target cell 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 Steps in CTL-mediated lysis of target cells Recognition of Antigen and Activation of CTLs Recognition of Antigen and Activation of CTLs Mechanisms of CTL-mediated lysis of target cells Fas/FasL pathway Granule exocytosis 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. Mechanisms of CTL-mediated lysis of target cells 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