分子免疫學t細胞亞群

1、,T 細胞亞群T 細胞活化機制T 細胞免疫應答及其效應,,,Phases of T cell responses,,priming,T cell subsets,?? T cells (~95%) and ?? T cells (~5%) CD4+T cells and CD8+T cells Naïve T cells（初始T細胞） Effector T cells （效應T細胞） Memo

2、ry 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 (Tregs) 調(diào)節(jié)性CD4+T細胞,,T Cell subsets,,Positive selection,Negative selection,T cell development in the thymus,,

3、,,,Phases of T cell responses,,priming,Naïve T cellsMature T cells that have not previously encountered antigen; Preferential migration to secondary lymphoid organs (lymph nodes), where they recognize antigen Ef

4、fector 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, functional

5、ly 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.,Central memory T cel

6、ls 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 n

7、ot 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 funct

8、ions.,Subsets of memory T cells,Nature Immunol, 2011, June, the reviews of memory T cell,,CD4+,CD8+,CD4+,,.,Effector T cell subsets,Th1-Th2 hypothesis 1986 Coffman and Mossman Th17 20

9、05 Tfh 2000,,Discovery of CD4+ Th cell subsets,,How they are induced, What cytokines they produce What effector mechanisms they activate,Th0,Th1,Th2,Th17,Humoral Immunity,,,,,Imm

10、une modulation,,The subsets of CD4+Th cells,,,Properties of CD4+ Th1 and Th2 subsets,,,Cytokines,Stimuli that influence the pattern of Th cell differentiation,TCR signal strength Different subsets of dendritic cells ma

11、y exist The genetic makeup of the host,,STAT: Signal transducer and activator of transcription,Differentiation of Th1 Subset,Stimulated by intracellular microbes that infect or activate macrophages or NK cells

12、 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

13、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

14、 IFN-? STAT-1 Ag recognition by TCR T-betA positive amplification loop between T-bet and IFN-?,,,,,,,,,Differentiation of Th2 Subset,Imp

15、ortant 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,Imp

16、ortant 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 S

17、TAT6,,,Development of Th1 and Th2 subsets,,Th2 cell differentiation requires both GATA3 expression and STAT5 activation,Nature Review Immunol, 2010,,,Differentiation of Th17 Subset,Stimulated by zymosan, fungus, myobacte

18、ria,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,,Steps in the differenti

19、ation of Th17 cells,,Conventional Th17 cell development,Immunologic Review , 2013,,Follicular helper T cells (TFH),Preferentially resident in B cell follicles Express CXCR5, a early defining marker Produce a large amou

20、nt 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 s

21、witched antibodies and B cell memory,,Anatomical localization and cellular requirements for Tfh cell generation,JEM, 2012,JEM, 2012,Anatomical localization and cellular requirements for Tfh cell generation,CD4+CD25+

22、 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,

23、,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 1

24、995,The Discovery of CD4+CD25+ Treg cells,Identify CD25 as a surface marker,The discovery of Foxp3 and its role in CD4+CD25+ Treg,Hori et al. Control of regulatory T cell development by the transcription factor Foxp3. S

25、cience 2003 Fontenot et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol 2003 R. Khattri, et al, An essential role for Scurfin in CD4+CD25+ T regulatory cells, Nat. Imm

26、unol. 4 (2003), pp. 337–342.,,,Natural Treg cells (nTreg) Thymic derived, highly controlled by thymic microenvironment Induced Treg cells (iTreg) Peripherally generated from Foxp3-CD4+T cells differen

27、tiated under more varied conditions,Subsets of Treg cells,,Thymic and Peripheral Generation of Foxp3+ Treg Cells,TCR Co-stimulation Cytokine-mediated signals,,Mechanisms of iTreg cells differentiation,TCR TGF-? IL-2

28、,,Nonregulatory naïve conventional CD4+T cells are able to acquire Foxp3 expression and regulatory function. The conversion can occur in both in vitro and in vivo Treg cells converted in vivo can be functionally

29、quite effective,,,Subsets “in the making”,Th9 Th22,,Th9,Veldhoen, M. et al. Transforming growth factor-β ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol

30、. 9, 1341–1346 (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, 1653–1660 (2009). Elyaman, W. et al. IL-9 i

31、nduces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl. Acad. Sci. USA 106, 12885–12890 (2009). Beriou et al. TGF-beta induces IL-9 from human Th17 cells. J Immunol.

32、 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, 857–863 (2009). Trifari, et al. Identification of a human helper T cell popu

33、lation that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nature Immunol. 10, 864–871 (2009).,Th22,In human, but not mouse Express IL-22 but not IL-17 or ROR-?t May present a

34、skin-homing subset responsible for skin inflammation such as psoriasis,,JEM, 2012,CD4+ T cell flexibility,A possible hierarchy of stability,,TGF? and IL-6 gradients regulate early Th17, iTreg, and Th22 commitment,,T

35、he 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?,Questio

36、ns?,Innate T cells,?? 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 (D

37、ETC) 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 repr

38、esent an important bridge between innate and adaptive immunity, functioning as lymphocytes that enhance the first line of defense against a range of pathogens.,,Six of the best γδ T cell functions,Nature Review Immunol,

39、2013,,Martin B et al. IL-17-Producing ?? T cells Selectively Expand in Response to Pathogen Products and Environmental Signals. Immunity 31, 321–330 (2009). They show that ?? T-17 cells additionally express IL-23R ,

40、 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 bact

41、eria 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

42、 innate IL-17 production from ?? T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009). This report shows that ?? T cells have an early role in promoting CNS inflammation. The authors sugg

43、est that innate cell-produced IL-17 directly enhances development of MOG-specific Th17 cells.,??T cells: a major innate source of IL-17,,Innate Activation of IL-17-Production by a Specialized ?? T Cell Subset,Kapsenberg