复旦大学课件T细胞亚群1017

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1、1T 细胞亚群细胞亚群 何睿何睿免疫学系免疫学系上海医学院上海医学院复旦大学复旦大学234Classes of lymphocytes5v T 细胞亚群细胞亚群v T 细胞活化分子机制细胞活化分子机制v T 细胞免疫应答及其效应细胞免疫应答及其效应v 自身免疫和超敏反应自身免疫和超敏反应6v T cell subsetsq T cells and T cells q CD4+T cells and CD8+Tq Nave T cells（初始（初始T细胞）细胞）Effector T cells（效应（效应T细胞）细胞）Memory T cells（记忆（记忆T细胞）细胞）q T helper(

2、Th)辅助性辅助性CD4+T细胞细胞 Cytotoxic T cells(CTLs)细胞毒性细胞毒性CD8+T细胞细胞 Regulatory T cells(Tregs)调节性调节性CD4+T细胞细胞7T Cell subsetsClassFunctionsAntigen receptor and specificitySelected markersPercent of total lymphocytes(human)T lymphocytes BloodLymph nodeSpleen CD4+helper T lymphocytesB cell differentiation(humor

3、al immunity)Macrophage activation(cell-mediated immunity)heterodimersDiverse specificities for peptide-class II MHC complexesCD3+,CD4+,CD8-50-60*50-6050-60 CD8+cytotoxic T lymphocytesKilling of cell infected with microbes,killing of tumor cells heterodimersDiverse specificities for peptide-class I M

4、HC complexesCD3+,CD4-,CD8+20-2515-2010-15Regulatory T cellsSuppress function of other T cells(regulation of immune responses,maintenance of self-tolerance)heterodimersCD3+,CD4+,CD25+(Most common,but other phenotypes as well)Rare1010 T lymphocytesHelper and cytotoxic functions(innate immunity)heterod

5、imersLimited specificities for peptide and nonpeptide antigensCD3+,CD4,and CD8 variable 8 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 recogn

6、ize 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

7、 first line of defense against a range of pathogens.9Jensen,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).p Epithelial T cell and Peripheral T cell p CD27-IL-17+T cells and CD27

8、+IFN-+T cells Subsets of T cells 10Developmental programming of T cell subsets.Cua DJ,et al.Nature review Immunology,201011u 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 additio

9、nally 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 role

10、s of T-17-derived may be indirect or direct amplification of IL-17 production in Th17 cells.u 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

11、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-1712Innate Activation of IL-17-Production by a Specialized T Cell SubsetKapsenberg ML.Immunity,200913u Witherden,et al.The junctional ad

12、hesion molecule JAML is a costimulatory receptor for epithelial T cell activation.Science 2010 SepIdentify an epithelial T cells-specific costimulatory molecule,JAMLu Petermann F,et al.T cells enhance autoimmunity by restraining regulatory T cells responses via an IL-23-dependeng mechanism.Immunity,

13、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 month1415q Nave T cells Mature T cells that have not previously

14、encountered antigen;Preferential migration to secondary lymphoid organs(lymph nodes),where they recognize antigenq 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-livedq M

15、emory 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.16Naive T cellsEffector T cellsMemory T cellsMigrationPreferentially t

16、o peripheral lymphoid tissuesPreferentially to inflamed tissuesPreferentially to inflamed tissues,mucosal tissuesFrequency of cells responsive to particular antigenVery lowHighLowEffector functionsNoneCytokine secretion;cytotoxic activityNoneCell cyclingNoYes+/-Surface protein expression High-affini

17、ty IL-2 receptorLowHighLowPeripheral lymph node homing receptor(L-selectin,CD62L)HighLowLow or variableAdhesion molecules:integrins,CD44LowHighHighChemokine receptor:CCR7HighLowVariableMajor CD45 isoform(humans only)CD45RACD45ROCD45RO;variableMorphologySmall;scant cytoplasmLarge;more cytoplasmSmall1

18、7u 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 u Effector memory T cells do not express CCR7 or L-selectin,and home to peripheral tissues,espe

19、cially mucosa.produce effector cytokines upon antigenic stimulation do not proliferate much.Based on their homing properties and effector functions.Subsets of memory T cells 18CD4+CD8+CD4+19 Th1-Th2 hypothesis 1986 Coffman and Mossman Th17 2006Discovery of CD4+Th cell subsets20The subsets of CD4+Th

20、cells How they are induced,What cytokines they produce What effector mechanisms they activate Th021q Cytokines Stimuli that influence the pattern of Th cell differentiationq High doses of antigen without adjuvants q Different subsets of dendritic cells may existq The genetic makeup of the host 22Pro

21、perties of CD4+Th1 and Th2 subsets23Differentiation of Th1 Subsetv Stimulated by intracellular microbes that infect or activate macrophages or NK cells Listeria,mycobacteria and Leishmaniav Important cytokines for the Th1 differentiationv Important transcription factors(TF)for the Th1 differentiatio

22、n IL-12 IFN-IL-18 type I IFNs (in human)T-bet:master regulator STAT4 STAT124The molecular basis of Th1 differentiationThe 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-betA positive amplifica

23、tion loop between T-bet and IFN-25Differentiation of Th1 subsets26Differentiation of Th2 Subsetv Important TF for the Th2 differentiationv Stimulated by microbes and antigens that cause persistent or repeated T cell stimulation with little inflammation or macrophage activation Helminth and allergens

24、 v Important cytokines for the Th2 differentiation IL-4 GATA-3:master regulator STAT627The molecular basis of Th2 differentiationThe interplay of signals from the T cell receptor,the cytokine IL-4,and the TF GATA-3 and STAT6Th2 differentiation is dependent on IL-4 IL-4 STAT-6 Ag recognition by TCR G

25、ATA-328GATA-3 q 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 q Enhances its own expression via a positive feedback loop q Blocks Th1 differentiation A master regulator of Th2 differentiati

26、on 29Development of Th2 subsets30Development of Th1 and Th2 subsets3132Differentiation of Th17 Subsetv Stimulated by zymosan,fungus,myobacteriav Important cytokines for the Th17 differentiationv Important transcription factors(TF)for the Th17 differentiation IL-6 TGF-IL-23 IL-21 ROR-t:master regulat

27、or ROR-STAT3 AhR33Th17 and AhRThe role of AhR in Th17 development and effector function revealed an environmental effect on Th17 generation.u Veldhoen et al.The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.Nature 453,106109(2008).u Quintana et al.Control of

28、 Treg and TH17 cell differentiation by the aryl hydrocarbon receptor.Nature 453,6571(2008).u 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).u Veldhoen,et al.Natural agonists for aryl hydroc

29、arbon 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 differentiation34The differentiation of Th17 Subset35CD4+CD25+Regulatory T cells(Treg cells)A subset of CD4+CD25+T cells expressing Foxp3 Naturally pre

30、sent in immune system,constitute 5-10%of peripheral CD4+T cells Suppress immune responses and maintain self-tolerance 36u 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 va

31、rious autoimmune diseases.J Immunol 1995u Hori et al.Control of regulatory T cell development by the transcription factor Foxp3.Science 2003u Fontenot et al.Foxp3 programs the development and function of CD4+CD25+regulatory T cells.Nature Immunol 2003Landmark papers about Treg37p Natural Treg cells(

32、nTreg)thymic derived,highly controlled by thymic microenvironmentp Induced Treg cells(iTreg)peripherally generatedSubsets of Treg cells 38l TCRl Co-stimulationl Cytokine-mediated signals39Josefowicz et al.Immunity,2009Differentiation of thymic and induced Treg cells40Mechanisms of Treg cells-mediate

33、d suppression 41p Directly suppress responder Foxp3-T cellsp Indirectly block the activation of Foxp3-T cells by suppressing the function of APC Mechanisms of Treg cells-mediated suppression 42Major mechanisms by which Treg cells can directly suppress responder Foxp3-T cellsShevach.Immunity,200943Ma

34、jor mechanisms by which Treg cells can suppress the function of APC and indirectly block of the activation of Foxp3-T cellsShevach.Immunity,20094445Subsets“in the making”p Follicular helper T cells(TFH)p Th9p Th2246Follicular helper T cells(TFH)Preferentially resident in B cell follicles Express CXC

35、R5 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 memory47u Vogelzang,et al.Generation of T

36、follicular helper cells is mediated by interleukin-21 but independent of T helper 1,2,or 17 cell lineages.Immunity 29,138149(2008).u Zaretsky,et al.T follicular helper cells differentiate from Th2 cells in response to helminth antigens.J.Exp.Med.206,991999(2009).u King et al.IL-4-producing CD4+T cel

37、ls in reactive lymph nodes during helminth infection are T follicular helper cells.J.Exp.Med.206,10011007(2009).u 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 i

38、nfection,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 folliclesu Johnston et al.Bcl6 and Blimp-1 are reciprocal and antagonistic regu

39、lators of T follicular helper cell differentiation.Science 325,10061010(2009).48Th9u 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

40、T cell typeu Nowak,E.C.et al.IL-9 as a mediator of Th17-driven inflammatory disease.J.Exp.Med.206,16531660(2009).u 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).u Beriou et al.TGF-beta

41、induces IL-9 from human Th17 cells.J Immunol.2010 4950u 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).u Trifari,et al.Identification of a human helper T cell population that has abundant production of in

42、terleukin 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 psoriasis5152A possible hierarchy of stability53p The flexibility of T cell subsets?p What are the environmental(extrinsic)factors that allow for plasticity?p What regulates lineage commitment versus flexibility?p Why do we need so many functional subsets?Questions