復旦大學課件T細胞亞群10-17.ppt

1、,T 細胞亞群,何睿 免疫學系 上海醫(yī)學院 復旦大學,Classes of lymphocytes,T 細胞亞群 T 細胞活化分子機制 T 細胞免疫應答及其效應,自身免疫和超敏反應,T cell subsets, T cells and T cells CD4+T cells and CD8+T Nave T cells（初始T細胞） Effector T cells （效應T細胞） Memory T cells （記憶T細胞） T helper (Th) 輔助性CD4+T細胞 Cytotoxic T cells (CTLs) 細胞毒性CD8+T細胞 Regulatory T cells (T

2、regs) 調節(jié)性CD4+T細胞,T Cell subsets, 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

3、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 pathog

4、ens.,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,Developme

5、ntal 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

6、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

7、 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 inflammatio

8、n. 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

9、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-act

10、ivated 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; P

11、referential 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-li

12、ved, 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.,Central memory T cells express CCR7 and L-selectin, and home to lymph nodes. limited c

13、apacity 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

14、 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

15、 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

16、 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 b

17、asis 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

18、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,Th

19、e 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,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 remo

20、deling 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 Th1

21、7 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 hydroc

22、arbon 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 par

23、ticipates 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 differe

24、ntiation,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 sel

25、f-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

26、 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-s

27、timulation 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,Mechani

28、sms 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,Subs

29、ets “in the making”,Follicular helper T cells (TFH) Th9 Th22,Follicular helper T cells (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

30、 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

31、. 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. Cyt

32、okine-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),

33、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-producin