復(fù)旦大學(xué)課件T細(xì)胞亞群10-17推薦資料

1、T 細(xì)胞亞群 何睿免疫學(xué)系上海醫(yī)學(xué)院復(fù)旦大學(xué)123Classes of lymphocytes4 T 細(xì)胞亞群 T 細(xì)胞活化分子機(jī)制 T 細(xì)胞免疫應(yīng)答及其效應(yīng) 自身免疫和超敏反應(yīng)5 T cell subsets T cells and T cells CD4+T cells and CD8+T Nave T cells（初始T細(xì)胞） Effector T cells （效應(yīng)T細(xì)胞） Memory T cells （記憶T細(xì)胞） T helper (Th) 輔助性CD4+T細(xì)胞 Cytotoxic T cells (CTLs) 細(xì)胞毒性CD8+T細(xì)胞 Regulatory T cells (Tr

2、egs) 調(diào)節(jié)性CD4+T細(xì)胞6T Cell subsetsClassFunctionsAntigen receptor and specificitySelected markersPercent of total lymphocytes (human) T lymphocytesBloodLymph nodeSpleenCD4+ helper T lymphocytesB cell differentiation (humoral immunity)Macrophage activation (cell-mediated immunity) heterodimersDiverse spec

3、ificities for peptide-class II MHC complexesCD3+, CD4+, CD8-50-60*50-6050-60CD8+ cytotoxic T lymphocytesKilling 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

4、 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) heterodimersLimited specificities for peptide and nonpeptide antigensCD3+,

5、 CD4, and CD8 variable7 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 restricte

6、d. 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. 8Jen

7、sen, 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 9Developmental pr

8、ogramming of T cell subsets.Cua DJ, et al. Nature review Immunology, 201010 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 recept

9、ors 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 di

10、rect 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

11、 authors suggest that innate cell-produced IL-17 directly enhances development of MOG-specific Th17 cells.A major innate source of IL-1711Innate Activation of IL-17-Production by a Specialized T Cell SubsetKapsenberg ML. Immunity,200912 Witherden,et al. The junctional adhesion molecule JAML is a cos

12、timulatory receptor for epithelial T cell activation. Science 2010 SepIdentify 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

13、 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 month1314 Nave T cellsMature T cells that have not previously encountered antigen; Prefe

14、rential migration to secondary lymphoid organs (lymph nodes), where they recognize antigen Effector T cellsActivated T cells capable of performing the functions required to eliminate foreign antigensPreferential migration to sites of infection or inflammationShort-lived Memory T cellsLong-lived, fun

15、ctionally 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. 15Naive T cellsEffector T cellsMemory T cellsMigrationPreferentially to peripheral lymphoid tiss

16、uesPreferentially to inflamed tissuesPreferentially to inflamed tissues, mucosal tissuesFrequency of cells responsive to particular antigenVery lowHighLowEffector functionsNoneCytokine secretion; cytotoxic activityNoneCell cyclingNoYes+/-Surface protein expressionHigh-affinity IL-2 receptorLowHighLo

17、wPeripheral lymph node homing receptor (L-selectin, CD62L)HighLowLow or variableAdhesion molecules: integrins, CD44LowHighHighChemokine receptor: CCR7HighLowVariableMajor CD45 isoform (humans only)CD45RACD45ROCD45RO; variableMorphologySmall; scant cytoplasmLarge; more cytoplasmSmall16 Central memory

18、 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.

19、produce effector cytokines upon antigenic stimulation do not proliferate much. Based on their homing properties and effector functions. Subsets of memory T cells 17CD4+CD8+CD4+18 Th1-Th2 hypothesis 1986 Coffman and Mossman Th17 2006Discovery of CD4+ Th cell subsets19The subsets of CD4+Th cells How t

20、hey are induced, What cytokines they produce What effector mechanisms they activate Th020 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 21Properties of CD4+

21、 Th1 and Th2 subsets22Differentiation 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- I

22、L-18 type I IFNs (in human) T-bet: master regulator STAT4 STAT123The 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 amplification

23、loop between T-bet and IFN-24Differentiation of Th1 subsets25Differentiation 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 Import

24、ant cytokines for the Th2 differentiation IL-4 GATA-3: master regulator STAT626The 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-32

25、7GATA-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 28Dev

26、elopment of Th2 subsets29Development of Th1 and Th2 subsets3031Differentiation 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 RO

27、R- STAT3 AhR32Th17 and AhRThe 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

28、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 a

29、ryl 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 differentiation33The differentiation of Th17 Subset34CD4+CD25+ Regulatory T cells (Treg cells) A subset of CD4+ CD25+ T cells expressing Fo

30、xp3 Naturally present in immune system, constitute 5-10% of peripheral CD4+ T cells Suppress immune responses and maintain self-tolerance 35 Sakaguchi et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of se

31、lf-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 2003Landmark papers about T

32、reg36 Natural Treg cells (nTreg) thymic derived, highly controlled by thymic microenvironment Induced Treg cells (iTreg) peripherally generatedSubsets of Treg cells 37 TCR Co-stimulation Cytokine-mediated signals38Josefowicz et al. Immunity, 2009Differentiation of thymic and induced Treg cells39Mech

33、anisms of Treg cells-mediated suppression 40 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 41Major mechanisms by which Treg cells can directly suppress responder Foxp3-T ce

34、llsShevach. Immunity, 200942Major mechanisms by which Treg cells can suppress the function of APC and indirectly block of the activation of Foxp3-T cellsShevach. Immunity, 20094344Subsets “in the making” Follicular helper T cells (TFH) Th9 Th2245Follicular helper T cells (TFH) Preferentially residen

35、t 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 memory46

36、 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, 9919

37、99 (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

38、 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).47Th9 Veldhoen, M. et al. Transforming growth factor- reprograms the dif