T细胞亚群最好漂亮免疫课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,T细胞亚群最好漂亮免疫课件,Classes of lymphocytes,T,细胞亚群,T,细胞活化分子机制,T,细胞免疫应答及其效应,自身免疫和超敏反应,T cell subsets,T cells and,T cells,CD4,+,T cells and CD8,+,T,Nave T cells,（初始,T,细胞）,Effector,T cells,（效应,T,细胞）,Memory T cells,（记忆,T,细胞）,T helper (,Th,),辅助性,CD4,+,T,细胞,Cytotoxic,T cells (,CTLs,),细胞毒性,CD8,+,T,细胞,Regulatory T cells (,Tregs,),调节性,CD4,+,T,细胞,T Cell subsets,Class,Functions,Antigen receptor and specificity,Selected markers,Percent of total lymphocytes (human), T lymphocytes,Blood,Lymph node,Spleen,CD4,+,helper T lymphocytes,B cell differentiation (humoral immunity)Macrophage activation (cell-mediated immunity), heterodimersDiverse specificities for peptide-class II MHC complexes,CD3,+, CD4,+, CD8,-,50-60*,50-60,50-60,CD8,+,cytotoxic T lymphocytes,Killing of cell infected with microbes, killing of tumor cells, heterodimersDiverse specificities for peptide-class I MHC complexes,CD3,+, CD4,-, CD8,+,20-25,15-20,10-15,Regulatory T cells,Suppress function of other T cells (regulation of immune responses, maintenance of self-tolerance), heterodimers,CD3,+, CD4,+, CD25,+,(Most common, but other phenotypes as well),Rare,10,10, T lymphocytes,Helper and cytotoxic functions (innate immunity), heterodimersLimited specificities for peptide and nonpeptide antigens,CD3,+, CD4, and CD8 variable,T cells,express a limited number of,TCRs,abundant in epithelial tissues of certain species:,in the small bowel mucosa and in the skin of mouse. In the skin, known as a,dendritic,epidermal T cell (DETC),do not recognize MHC-associated peptide antigens and are not MHC restricted.,may bind to conserved,ligands,whose expression is triggered by cell injury or stress, such as microbial heat shock proteins.,may represent an important bridge between innate and adaptive immunity, functioning as lymphocytes that enhance the first line of defense against a range of pathogens.,Jensen, K. D.,et al,. Thymic selection determines,T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon,Immunity,29, 90100 (2008).,Epithelial,T cell,and,Peripheral,T cell,CD27,-,IL-17,+,T cells,and,CD27,+,IFN-,+,T cells,Subsets of ,T cells,Developmental programming of,T cell subsets,.,Cua DJ, et al. Nature review Immunology, 2010,Martin B et al.,IL-17-Producing,T cells Selectively Expand in Response to Pathogen Products and Environmental Signals.,Immunity,31, 321330 (2009).,They show that,T-17 cells additionally express IL-23R , and the innate receptors TLR2 and dectin-1, which recognize archetypical and fungal constituents. These,T-17 cells use these receptors to rapidly produce IL-17 in response to bystander cell-derived IL-23 and to bacteria and fungi without concomitant TCR stimulation. One of the roles of,T-17-derived may be indirect or direct amplification of IL-17 production in Th17 cells.,Sutton, C. E.,et al,.,Interleukin-1 and IL-23 induce innate IL-17 production from,T cells, amplifying Th17 responses and autoimmunity,.,Immunity,31, 331341 (2009).,This report shows that,T cells have an early role in promoting CNS inflammation. The authors suggest that innate cell-produced IL-17 directly enhances development of MOG-specific Th17 cells,.,A major innate source of IL-17,Innate Activation of IL-17-Production by a Specialized,T Cell Subset,Kapsenberg ML. Immunity,2009,Witherden,et al.,The,junctional,adhesion molecule JAML is a,costimulatory,receptor for epithelial,T cell activation,.,Science 2010 Sep,Identify an epithelial,T cells-specific,costimulatory,molecule, JAML,Petermann F, et al.,T cells enhance autoimmunity by restraining regulatory T cells responses via an IL-23-dependeng mechanism,.,Immunity, 2010 Sep,IL-23-activated render,effector,T cells refractory to the suppressive activity of,Treg,cells and also prevented the conversion of conventional T cells into Foxp3+Treg cells in vivo.,Two new papers about,T Cell published in this month,Nave T cells,Mature T cells that have not previously encountered antigen;,Preferential migration to secondary lymphoid organs (lymph nodes), where they recognize antigen,Effector,T cells,Activated T cells capable of performing the functions required to eliminate foreign antigens,Preferential migration to sites of infection or inflammation,Short-lived,Memory T cells,Long-lived, functionally silent cells;,Mount rapid secondary immune responses to the same antigen exposure,Heterogenous,(central and,effector,),Based on the history of antigen encounter and the stage of T cell activation.,Naive T cells,Effector T cells,Memory T cells,Migration,Preferentially to peripheral lymphoid tissues,Preferentially to inflamed tissues,Preferentially to inflamed tissues, mucosal tissues,Frequency of cells responsive to particular antigen,Very low,High,Low,Effector functions,None,Cytokine secretion; cytotoxic activity,None,Cell cycling,No,Yes,+/-,Surface protein expression,High-affinity IL-2 receptor,Low,High,Low,Peripheral lymph node homing receptor (L-selectin, CD62L),High,Low,Low or variable,Adhesion molecules: integrins, CD44,Low,High,High,Chemokine receptor: CCR7,High,Low,Variable,Major CD45 isoform (humans only),CD45RA,CD45RO,CD45RO; variable,Morphology,Small; scant cytoplasm,Large; more cytoplasm,Small,Central memory T cells,express CCR7 and L-,selectin, and home to lymph nodes.,limited capacity to perform,effector,functions when they encounter antigen,generate many,effector,cells upon antigen challenge,Effector,memory T cells,do not express CCR7 or L-,selectin, and home to peripheral tissues, especially,mucosa.,produce,effector,cytokines upon antigenic stimulation,do not proliferate much.,Based on their,homing properties and effector functions.,Subsets of memory,T cells,CD4,+,CD8,+,CD4,+,Th1-Th2 hypothesis 1986 Coffman and Mossman,Th17 2006,Discovery of CD4,+,Th cell subsets,The subsets of CD4,+,Th cells,How they are induced,What cytokines they produce,What,effector,mechanisms they activate,Th0,Cytokines,Stimuli that influence the pattern of Th cell differentiation,High doses of antigen without,adjuvants,Different subsets of,dendritic,cells may exist,The genetic makeup of the host,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,Important,transcription factors (,TF) for the Th1 differentiation,IL-12,IFN-,IL-18,type I,IFNs,(in human),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-, STAT-1,Ag recognition by TCR T-bet,A positive amplification loop between T-bet and IFN-,Differentiation of Th1 subsets,Differentiation of Th2 Subset,Important TF for the Th2 differentiation,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 Th2 differentiation,IL-4,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 STAT-6,Ag recognition by TCR GATA-3,GATA-3,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,A master regulator of Th2 differentiation,Development of Th2 subsets,Development of Th1 and Th2 subsets,Differentiation of Th17 Subset,Stimulated by,zymosan, fungus,myobacteria,Important cytokines for the Th17 differentiation,Important,transcription factors (,TF) for the Th17 differentiation,IL-6,TGF-,IL-23,IL-21,ROR-,t,: master regulator,ROR-,STAT3,AhR,Th17 and AhR,The role of AhR in Th17 development and effector function revealed an environmental effect on Th17 generation.,Veldhoen,et al.,The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.,Nature,453, 106109 (2008).,Quintana et al.,Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor.,Nature,453, 6571 (2008).,Kimura et al.,Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells,.,Proc. Natl. Acad. Sci. USA,105, 97219726 (2008).,Veldhoen, et al.,Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells,. J Exp Med, 2009,IMDM is better than 1640 for Th17 in vitro differentiation,The differentiation of Th17 Subset,CD4,+,CD25,+,Regulatory T cells (Treg cells),A subset of CD4,+,CD25,+,T cells expressing Foxp3,Naturally present in immune system, constitute 5-10% of,peripheral CD4,+,T cells,Suppress immune responses and maintain self-tolerance,Sakaguchi et al.,Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases,. J,Immunol,1995,Hori et al.,Control of regulatory T cell development by the transcription factor Foxp3,. Science 2003,Fontenot et al.,Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.,Nature,Immunol,2003,Landmark papers about Treg,Natural,Treg,cells (,nTreg,),thymic,derived, highly controlled by,thymic,microenvironment,Induced,Treg,cells (,iTreg,),peripherally generated,Subsets of,Treg cells,TCR,Co-stimulation,Cytokine-mediated signals,Josefowicz et al. Immunity, 2009,Differentiation of thymic and induced Treg cells,Mechanisms of,Treg cells-mediated suppression,Directly suppress responder Foxp3,-,T cells,Indirectly block the activation of Foxp3,-,T cells by,suppressing the function of APC,Mechanisms of,Treg cells-mediated suppression,Major mechanisms by which Treg cells can directly suppress responder Foxp3,-,T cells,Shevach. Immunity, 2009,Major mechanisms by which Treg cells can suppress the function of APC and indirectly block of the activation of Foxp3-T cells,Shevach. Immunity, 2009,Subsets “in the making”,Follicular helper T cells (T,FH,),Th9,Th22,Follicular helper T cells (T,FH,),Preferentially resident in B cell follicles,Express CXCR5,Produce a large amount of IL-21, which acts in an,autocrine,manner together with IL-6 promote their differentiation and expansion,Depend on the Bcl-6 transcription factor,Essential for the generation of high-affinity,isotype,switched antibodies,and B cell memory,Vogelzang, et al.,Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages.,Immunity,29, 138149 (2008).,Zaretsky, et al.,T follicular helper cells differentiate from Th2 cells in response to helminth antigens,.,J. Exp. Med.,206, 991999 (2009).,King et al.,IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells.,J. Exp. Med.,206, 10011007 (2009).,Rainhardt et al.,Cytokine-secreting follicular T cells shape the antibody repertoire,.,Nature Immunol.,10, 385393 (2009).,Three studies used IL-4 reporter mice and showed that, during helminth infection, most IL-4-expressing CD4+ T cells also expressed the TFH cell markers CXCR5, programmed cell death protein 1 (PD-1), inducible T cell co-stimulator(ICOS), B cell lymphoma 6(BCL-6) and,IL,-21 and localized to the B cell follicles,Johnston et al.,Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation,.,Science,325, 10061010 (2009).,Th9,Veldhoen, M.,et al,.,Transforming growth factor- reprograms the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset,.,Nat.,Immunol,.,9, 13411346 (2008).,Th2 cells can change into an IL-9-producing T cell type,Nowak, E.C.,et al,.,IL-9 as a mediator of Th17-driven inflammatory disease.,J. Exp. Med.,206, 16531660 (2009).,Elyaman, W.,et al,.,IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells,.,Proc. Natl. Acad. Sci. USA,106, 1288512890 (2009).,Beriou,et al.,TGF-beta induces IL-9 from human Th17 cells,. J,Immunol,. 2010,Duhen, et al.,Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells,.,Nature Immunol.,10, 857863 (2009).,Trifari, et al.,Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells.,Nature Immunol.,10, 864871 (2009).,Th22,In human, but not mouse,Express IL-22 but not IL-17 or ROR-,t:,May present a skin-homing subset responsible for skin inflammation,such as psoriasis,A possible hierarchy of stability,The flexibility of T cell subsets?,What are the environmental (extrinsic) factors that allow for,plasticity?,What regulates lineage commitment versus flexibility?,Why do we need so many functional subsets?,Questions,