分子免疫学T细胞免疫应答机制硕士教育.ppt

,识别,活化,效应,免疫应答的三个阶段,Overview of generation of T cell and T cell responses in vivo,Types of adaptive immune responses,.,T cell subsets,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,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 CD4+ Th17 responses extracellular bacteria, fungi,Different types of microbes elicit distinct protective T cell responses,Defects in CMI result in increased susceptibility to infection by viruses and intracellular bacteria,Types of T cell-mediated immune response,Major mediators of T cell-mediated immune responses,Cytokines Membrane proteins TNF family members: CD40L, TNF-, FasL,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,T cell signals that activate macrophages,IFN- CD40L-CD40 interactions,Central role of Th1 in the activation of macrophage,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,CD40L/CD40,Deliver contact-mediated signals activates the transcription factors nuclear factor KB (NF-KB) and activation protein-1 (AP-1) Increases the response to IFN- 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 Become the more efficient APCs Stimulation of acute inflammation Tissue Repair,Activation and functions of macrophages in CMI,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 orchestration of macrophage activation and polarization by Th cells,Biswas S, et al. Nature Immunol, 2010,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,Th17-Mediated Immune Responses,Th17-specific cytokines,IL-17A IL-17F IL-22,Effects of Interleukin-17 on Cell Functions and Its Role in the Pathophysiology of Diseases.,IL-22,Proinflammatory and protective properties,Proinflammatory role in psoriasis, RA and some infection,Protective role in IBD, infection, and liver injury,OConnor Jr et al. Nature Immunol 2010,A simplified model for pleiotropic TH17 cytokines in coordinating inflammation,protection,Chronic inflammation,Bettelli E, T Korn, M Oukka, and VK Kuchroo. Induction and effector functions of TH17 cells. Nature 453:1051-1057, 2008 Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nature Reviews Immunology 8:337-348, 2008. Farrar JD, H Asnagli, and KM Murphy. T helper subset development: roles of instruction, selection, and transcription. Journal of Clinical Investigation 109:431-435, 2002. Korn T, E Bettelli, M Oukka, and UK Kuchroo. IL-17 and Th17 cells. Annual Review of Immunology 27, 2009 McGeachy MJ, and DJ Cua. Th17 cell differentiation: the long and winding road. Immunity 28:445-453, 2008. Ouyang W, JK Kolls, and Y Zheng. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454-467, 2008.,Selected readings,Cytotoxic T Lymphocytes (CTLs),Effector CD8+ T Cells Eliminate intracellular microbes mainly by killing infected cells,CTL induce the apoptosis of target cells,Antigen specific Only kill targets that express the same class I-associated antigen that triggered their differentiation from nave CD8+ T cell Contact dependent The formation of immunological synapse The specific delivery of the molecules,CTL-mediated cytotoxcity,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,Mechanisms of CTL-mediated lysis of target cells,Granule exocytosis Fas/FasL pathway,Only human,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.,The two important granule proteins f