分子免疫學(xué)t細(xì)胞免疫應(yīng)答機(jī)制碩士教育

1、,,,識(shí)別,活化,,,效應(yīng),免疫應(yīng)答的三個(gè)階段,,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 respo

2、nses,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 th

3、e 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…..,Di

4、fferent 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

5、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

6、 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 ce

7、lls,,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 ma

8、jor 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 signa

9、ls activates the transcription factors nuclear factor KB (NF-KB) and activation protein-1 (AP-1) Increases the response to IFN-?Clinical evidenceHumans with inherited mutations in CD40L (X-linked hyper-IgM syndrome

10、) : 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 R

11、epair,,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

12、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,

13、,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 microbe

14、s 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 o

15、f 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

16、, 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

17、 and protective properties,Proinflammatory role in psoriasis, RA and some infection,Protective role in IBD, infection, and liver injury,,O'Connor Jr et al. Nature Immunol 2010,A simplified model for pleiotropic TH17

18、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 dev

19、elopment: 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, selectio

20、n, 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 di

21、fferentiation: 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

22、 readings,Cytotoxic T Lymphocytes (CTLs),Effector CD8+ T CellsEliminate intracellular microbes mainly by killing infected cells,,CTL induce the apoptosis of target cells,Antigen specific Only kill targets that expres

23、s 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,

24、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 c

25、ell,,Steps in CTL-mediated lysis of target cells,Mechanisms of CTL-mediated lysis of target cells,Granule exocytosisFas/FasL pathway,Only human,,Perforin a pore-forming protein molecule Main function is t

26、o 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 importan

27、t granule proteins for CTL killing function,,Mechanisms of CTL-mediated lysis of target cells,Cytokines secreted by CTL,,IFN-?TNF-?TNF-?,The different types of effector T cell subsets produce different effector molecul

28、es,IL-22,,Bossi G, and GM Griffiths. CTL secretory lysosomes: biogenesis and secretion of a harmful organelle. Seminars in Immunology 17:87-94, 2005 Gordon S. Alternative activation of macrophages. Nature Reviews Immun