T細(xì)胞亞群最好的漂亮免疫PPT學(xué)習(xí)教案

1、會(huì)計(jì)學(xué)1T細(xì)胞亞群最好的漂亮免疫細(xì)胞亞群最好的漂亮免疫第1頁/共53頁第2頁/共53頁Classes of lymphocytes第3頁/共53頁v T 細(xì)胞亞群細(xì)胞亞群v T 細(xì)胞活化分子機(jī)制細(xì)胞活化分子機(jī)制v T 細(xì)胞免疫應(yīng)答及其效應(yīng)細(xì)胞免疫應(yīng)答及其效應(yīng)v 自身免疫和超敏反應(yīng)自身免疫和超敏反應(yīng)第4頁/共53頁v T cell subsetsq T cells and T cells q CD4+T cells and CD8+Tq Nave T cells（初始（初始T細(xì)胞）細(xì)胞） Effector T cells （效應(yīng)（效應(yīng)T細(xì)胞）細(xì)胞） Memory T cells （記憶（記憶T細(xì)

2、胞）細(xì)胞）q T helper (Th) 輔助性輔助性CD4+T細(xì)胞細(xì)胞 Cytotoxic T cells (CTLs) 細(xì)胞毒性細(xì)胞毒性CD8+T細(xì)胞細(xì)胞 Regulatory T cells (Tregs) 調(diào)節(jié)性調(diào)節(jié)性CD4+T細(xì)胞細(xì)胞第5頁/共53頁T Cell subsetsClassFunctionsAntigen receptor and specificitySelected markersPercent of total lymphocytes (human) T lymphocytes BloodLymph nodeSpleen CD4+ helper T lymphoc

3、ytesB 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 lymphocytesKilling of cell infected with microbes, killing of tumor cells heterodimersDive

4、rse 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+, CD25+ (Most common, but other phenotypes as well)Rare1010 T lymphocytesHelper

5、 and cytotoxic functions (innate immunity) heterodimersLimited specificities for peptide and nonpeptide antigensCD3+, CD4, and CD8 variable 第6頁/共53頁 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

6、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, such as microbial heat shock proteins. may represent an important bridge between innat

7、e and adaptive immunity, functioning as lymphocytes that enhance the first line of defense against a range of pathogens. 第7頁/共53頁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, 9

8、0100 (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頁/共53頁Developmental programming of T cell subsets.Cua DJ, et al. Nature review Immunology, 2010第9頁/共53頁u Martin B et al. IL-17-Producing T cells Selectively Expand in Response to

9、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 recognize archetypical and fungal constituents. These T-17 cells use these receptors to rapidly produce IL-17 in response

10、 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 production in Th17 cells.u Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from T cells, ampli

11、fying 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-produced IL-17 directly enhances development of MOG-specific Th17 cells.A major innate source of IL-17第10頁/共53頁Inna

12、te Activation of IL-17-Production by a Specialized T Cell SubsetKapsenberg ML. Immunity,2009第11頁/共53頁u Witherden,et al. The junctional adhesion molecule JAML is a costimulatory receptor for epithelial T cell activation. Science 2010 SepIdentify an epithelial T cells-specific costimulatory molecule,

13、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-activated render effector T cells refractory to the suppressive activity of Treg cells and also prevented the conversion of conventional T cel

14、ls into Foxp3+Treg cells in vivo.Two new papers about T Cell published in this month第12頁/共53頁第13頁/共53頁q Nave T cellsMature T cells that have not previously encountered antigen; Preferential migration to secondary lymphoid organs (lymph nodes), where they recognize antigenq Effector T cellsActivated

15、T cells capable of performing the functions required to eliminate foreign antigensPreferential migration to sites of infection or inflammationShort-livedq Memory T cellsLong-lived, functionally silent cells; Mount rapid secondary immune responses to the same antigen exposureHeterogenous (central and

16、 effector)Based on the history of antigen encounter and the stage of T cell activation. 第14頁/共53頁Naive T cellsEffector T cellsMemory T cellsMigrationPreferentially to peripheral lymphoid tissuesPreferentially to inflamed tissuesPreferentially to inflamed tissues, mucosal tissuesFrequency of cells re

17、sponsive to particular antigenVery lowHighLowEffector functionsNoneCytokine secretion; cytotoxic activityNoneCell cyclingNoYes+/-Surface protein expression High-affinity IL-2 receptorLowHighLowPeripheral lymph node homing receptor (L-selectin, CD62L)HighLowLow or variableAdhesion molecules: integrin

18、s, CD44LowHighHighChemokine receptor: CCR7HighLowVariableMajor CD45 isoform (humans only)CD45RACD45ROCD45RO; variableMorphologySmall; scant cytoplasmLarge; more cytoplasmSmall第15頁/共53頁u Central memory T cells express CCR7 and L-selectin, and home to lymph nodes. limited capacity to perform effector

19、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, especially mucosa. produce effector cytokines upon antigenic stimulation do not proliferate much. Based on their homi

20、ng properties and effector functions. Subsets of memory T cells 第16頁/共53頁CD4+CD8+CD4+第17頁/共53頁 Th1-Th2 hypothesis 1986 Coffman and Mossman Th17 2006Discovery of CD4+ Th cell subsets第18頁/共53頁The subsets of CD4+Th cells How they are induced, What cytokines they produce What effector mechanisms they ac

21、tivate Th0第19頁/共53頁q 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 第20頁/共53頁P(yáng)roperties of CD4+ Th1 and Th2 subsets第21頁/共53頁Differentiation of Th1 Subset

22、v 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 differentiation IL-12 IFN- IL-18 type I IFNs (in human) T-bet: master regula

23、tor STAT4 STAT1第22頁/共53頁The 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 loop between T-bet and IFN- 第23頁/共53頁Diff

24、erentiation of Th1 subsets第24頁/共53頁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

25、Th2 differentiation IL-4 GATA-3: master regulator STAT6第25頁/共53頁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頁/共53頁GATA-3

26、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 differentiation 第27頁/共5

27、3頁Development of Th2 subsets第28頁/共53頁Development of Th1 and Th2 subsets第29頁/共53頁第30頁/共53頁Differentiation 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-

28、21 ROR- t: master regulator ROR- STAT3 AhR第31頁/共53頁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 autoimmunity to environmental toxins. Nature 453, 1061

29、09 (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. Proc. Natl. Acad. Sci. USA 105, 97219726 (2008).

30、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頁/共53頁The differentiation of Th17 Subset第33頁/共53頁CD4+CD25+ Regulatory T cells (T

31、reg 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頁/共53頁u Sakaguchi et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 rece

32、ptor 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. Science 2003u Fontenot et al. Foxp3 programs the development and function of CD4+CD2

33、5+ regulatory T cells. Nature Immunol 2003Landmark papers about Treg第35頁/共53頁p Natural Treg cells (nTreg) thymic derived, highly controlled by thymic microenvironmentp Induced Treg cells (iTreg) peripherally generatedSubsets of Treg cells 第36頁/共53頁l TCRl Co-stimulationl Cytokine-mediated signals第37頁

34、/共53頁Josefowicz et al. Immunity, 2009Differentiation of thymic and induced Treg cells第38頁/共53頁Mechanisms of Treg cells-mediated suppression 第39頁/共53頁p Directly suppress responder Foxp3- T cellsp Indirectly block the activation of Foxp3- T cells by suppressing the function of APC Mechanisms of Treg c

35、ells-mediated suppression 第40頁/共53頁Major mechanisms by which Treg cells can directly suppress responder Foxp3-T cellsShevach. Immunity, 2009第41頁/共53頁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

36、頁/共53頁第43頁/共53頁Subsets “in the making”p Follicular helper T cells (TFH)p Th9p Th22第44頁/共53頁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

37、 expansion Depend on the Bcl-6 transcription factor Essential for the generation of high-affinity isotype switched antibodies and B cell memory第45頁/共53頁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. Imm

38、unity 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 cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med.

39、 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 infection, most IL-4-expressing CD4+ T cells also expressed the TFH cell markers CXCR

40、5, 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 regulators of T follicular helper cell differentiation. Science 325, 10061010 (2009).第46頁/共53頁Th9u Veldhoen, M. et al. Transforming growth factor- reprograms the