T细胞亚群最好的漂亮免疫学习教案VIP

1、会计学1T细胞亚群最好的漂亮细胞亚群最好的漂亮(pio ling)免疫免疫第一页，共54页。第1页/共53页第二页，共54页。第2页/共53页第三页，共54页。Classes of lymphocytes第3页/共53页第四页，共54页。v 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(jzh)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(zshn)免疫和超敏反应第4页/共53页第五页，共54页。v 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

2、胞）q Effector T cells （效应（效应(xioyng)T细胞）细胞）q Memory T cells （记忆（记忆T细胞）细胞）q T helper (Th) 辅助性辅助性CD4+T细胞细胞q Cytotoxic T cells (CTLs) 细胞毒性细胞毒性CD8+T细胞细胞q Regulatory T cells (Tregs) 调节性调节性CD4+T细胞细胞第5页/共53页第六页，共54页。T Cell subsetsClassFunctionsAntigen receptor and specificitySelected markersPercent of total

3、 lymphocytes (human) T lymphocytes BloodLymph nodeSpleen CD4+ helper T lymphocytesB cell differentiation (humoral immunity)Macrophage activation (cell-mediated immunity) heterodimersDiverse specificities for peptide-class II MHC complexesCD3+, CD4+, CD8-50-60*50-6050-60 CD8+ cytotoxic T lymphocytesK

4、illing of cell infected with microbes, killing of tumor cells heterodimersDiverse specificities for peptide-class I MHC complexesCD3+, CD4-, CD8+20-2515-2010-15Regulatory T cellsSuppress function of other T cells (regulation of immune responses, maintenance of self-tolerance) heterodimersCD3+, CD4+,

5、 CD25+ (Most common, but other phenotypes as well)Rare1010 T lymphocytesHelper and cytotoxic functions (innate immunity) heterodimersLimited specificities for peptide and nonpeptide antigensCD3+, CD4, and CD8 variable 第6页/共53页第七页，共54页。 T cells express a limited number of TCRs abundant in epithelial

6、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,

7、 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. 第7页/共53页第八页，共54页。Jensen, K. D. et al. Thymic selection determines T cell effector fate: anti

8、gen-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+IFN- + T cells Subsets of T cells 第8页/共53页第九页，共54页。Developmental programming of T cell subsets.Cua DJ, et al. Nature re

9、view Immunology, 2010第9页/共53页第十页，共54页。u 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 recogni

10、ze 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 producti

11、on 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 promoting CNS inflammation. The authors suggest that innate cell-p

12、roduced IL-17 directly enhances development of MOG-specific Th17 cells.A major innate source of IL-17第10页/共53页第十一页，共54页。Innate Activation of IL-17-Production by a Specialized T Cell SubsetKapsenberg ML. Immunity,2009第11页/共53页第十二页，共54页。u Witherden,et al. The junctional adhesion molecule JAML is a cos

13、timulatory 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, 2010 Sep IL-23-activate

14、d 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第12页/共53页第十三页，共54页。第13页/共53页第十四页，共54页。q Nave T cellsMature T cells that have not p

15、reviously encountered antigen; Preferential migration to secondary lymphoid organs (lymph nodes), where they recognize antigenq Effector T cellsActivated T cells capable of performing the functions required to eliminate foreign antigensPreferential migration to sites of infection or inflammationShor

16、t-livedq Memory T cellsLong-lived, functionally silent cells; Mount rapid secondary immune responses to the same antigen exposureHeterogenous (central and effector)Based on the history of antigen encounter and the stage of T cell activation. 第14页/共53页第十五页，共54页。Naive T cellsEffector T cellsMemory T c

17、ellsMigrationPreferentially to peripheral lymphoid tissuesPreferentially to inflamed tissuesPreferentially to inflamed tissues, mucosal tissuesFrequency of cells responsive to particular antigenVery lowHighLowEffector functionsNoneCytokine secretion; cytotoxic activityNoneCell cyclingNoYes+/-Surface

18、 protein expression High-affinity IL-2 receptorLowHighLowPeripheral lymph node homing receptor (L-selectin, CD62L)HighLowLow or variableAdhesion molecules: integrins, CD44LowHighHighChemokine receptor: CCR7HighLowVariableMajor CD45 isoform (humans only)CD45RACD45ROCD45RO; variableMorphologySmall; sc

19、ant cytoplasmLarge; more cytoplasmSmall第15页/共53页第十六页，共54页。u 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 exp

20、ress 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 第16页/共53页第十七页，共54页。CD4+CD8+CD4+第17页/共53页第十八页，共54页。 Th1-Th2 hyp

21、othesis 1986 Coffman and Mossman Th17 2006Discovery of CD4+ Th cell subsets第18页/共53页第十九页，共54页。The subsets of CD4+Th cells How they are induced, What cytokines they produce What effector mechanisms they activate Th0第19页/共53页第二十页，共54页。q Cytokines Stimuli that influence the pattern of Th cell different

22、iationq High doses of antigen without adjuvants q Different subsets of dendritic cells may existq The genetic makeup of the host 第20页/共53页第二十一页，共54页。Properties of CD4+ Th1 and Th2 subsets第21页/共53页第二十二页，共54页。Differentiation of Th1 Subsetv Stimulated by intracellular microbes that infect or activate m

23、acrophages or NK cells Listeria, mycobacteria and Leishmaniav Important cytokines for the Th1 differentiationv Important transcription factors (TF) for the Th1 differentiation IL-12 IFN- IL-18 type I IFNs (in human) T-bet: master regulator STAT4 STAT1第22页/共53页第二十三页，共54页。The molecular basis of Th1 di

24、fferentiationThe 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 amplification loop between T-bet and IFN- 第23页/共53页第二十四页，共54页。Differentiation of Th1 subsets第24页/共53页第二十五页，共

25、54页。Differentiation 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 v Important cytokines for the Th2 differentiation IL-4 GATA-3

26、: master regulator STAT6第25页/共53页第二十六页，共54页。The 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 GATA-3第26页/共53页第二十七页，共54页。GATA-3 q Enhance

27、s 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 differentiation 第27页/共53页第二十八页，共

28、54页。Development of Th2 subsets第28页/共53页第二十九页，共54页。Development of Th1 and Th2 subsets第29页/共53页第三十页，共54页。第30页/共53页第三十一页，共54页。Differentiation of Th17 Subsetv Stimulated by zymosan, fungus, myobacteriav Important cytokines for the Th17 differentiationv Important transcription factors (TF) for the Th17 d

29、ifferentiation IL-6 TGF- IL-23 IL-21 ROR- t: master regulator ROR- STAT3 AhR第31页/共53页第三十二页，共54页。Th17 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 autoimmun

30、ity to environmental toxins. Nature 453, 106109 (2008).u Quintana et al. Control of 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. Pro

31、c. Natl. Acad. Sci. USA 105, 97219726 (2008).u 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第32页/共53页第三十三页，共54页。The differentiatio

32、n of Th17 Subset第33页/共53页第三十四页，共54页。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 第34页/共53页第三十五页，共54页。u Sakaguchi et al. I

33、mmunologic 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 1995u Hori et al. Control of regulatory T cell development by the transcription factor Foxp3. Scienc

34、e 2003u Fontenot et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol 2003Landmark papers about Treg第35页/共53页第三十六页，共54页。p Natural Treg cells (nTreg) thymic derived, highly controlled by thymic microenvironmentp Induced Treg cells (iTreg) peripherally gen

35、eratedSubsets of Treg cells 第36页/共53页第三十七页，共54页。l TCRl Co-stimulationl Cytokine-mediated signals第37页/共53页第三十八页，共54页。Josefowicz et al. Immunity, 2009Differentiation of thymic and induced Treg cells第38页/共53页第三十九页，共54页。Mechanisms of Treg cells-mediated suppression 第39页/共53页第四十页，共54页。p Directly suppress

36、 responder Foxp3- T cellsp Indirectly block the activation of Foxp3- T cells by suppressing the function of APC Mechanisms of Treg cells-mediated suppression 第40页/共53页第四十一页，共54页。Major mechanisms by which Treg cells can directly suppress responder Foxp3-T cellsShevach. Immunity, 2009第41页/共53页第四十二页，共5

37、4页。Major mechanisms by which Treg cells can suppress the function of APC and indirectly block of the activation of Foxp3-T cellsShevach. Immunity, 2009第42页/共53页第四十三页，共54页。第43页/共53页第四十四页，共54页。Subsets “in the making”p Follicular helper T cells (TFH)p Th9p Th22第44页/共53页第四十五页，共54页。Follicular helper T ce

38、lls (TFH) 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 switche

39、d antibodies and B cell memory第45页/共53页第四十六页，共54页。u 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). u Zaretsky, et al. T follicular helper cells differentiate from Th2 cells in

40、response to helminth antigens. J. Exp. Med. 206, 991999 (2009).u 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).u Rainhardt et al. Cytokine-secreting follicular T cells shape the antibody repe

41、rtoire. 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

42、-6) and IL-21 and localized to the B cell folliclesu Johnston et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 10061010 (2009).第46页/共53页第四十七页，共54页。Th9u 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, 134113