分子免疫学-T细胞亚群 0硕士ppt课件

1、vT 细胞亚群细胞亚群vT 细胞活化机制细胞活化机制vT 细胞免疫应对及其效应细胞免疫应对及其效应Phases of T cell responsesprimingv T cell subsetsq T cells (95%) and T cells (5%) q CD4+T cells and CD8+T cellsq Nave T cells初始初始T细胞细胞q Effector T cells 效应效应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

2、胞毒性CD8+T细胞细胞q Regulatory T cells (Tregs) 调理性调理性CD4+T细胞细胞T Cell subsetsClassFunctionsAntigen receptor and specificitySelected markersPercent of total lymphocytes (human) T lymphocytesBloodLymph nodeSpleen CD4+ helper T lymphocytesB cell differentiation (humoral immunity)Macrophage activation (cell-me

3、diated 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 heterodimersDiverse specificities for peptide-class I MHC complexesCD3+, CD4-, CD8+20-2515-

4、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 and cytotoxic functions (innate immunity) heterodimersLimited specificitie

5、s for peptide and nonpeptide antigensCD3+, CD4, and CD8 variable Positive selectionNegative selectionT cell development in the thymusPhases of T cell responsesprimingq Nave T cellsq Mature T cells that have not previously encountered antigen; q Preferential migration to secondary lymphoid organs (ly

6、mph nodes), where they recognize antigenq Effector T cellsq Activated T cells capable of performing the functions required to eliminate foreign antigensq Preferential migration to sites of infection or inflammationq Short-livedq Memory T cellsq Long-lived, functionally silent cells; q Mount rapid se

7、condary immune responses to the same antigen exposureq Heterogenous (central and effector)Based on the history of antigen encounter and the stage of T cell activation. Naive T cellsEffector T cellsMemory T cellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferen

8、tiallytoinflamedtissues,mucosaltissuesFrequency of cells responsive to particular antigenVerylowHighLowEffector functionsNoneCytokinesecretion;cytotoxicactivityNoneCell cyclingNoYes+/-Surface protein expressionHigh-affinity IL-2 receptorLowHighLowPeripheral lymph node homing receptor (L-selectin, CD

9、62L)HighLowLoworvariableAdhesion molecules: integrins, CD44LowHighHighChemokine receptor: CCR7HighLowVariableMajor CD45 isoform (humans only)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmallu Central memory T cellsu express CCR7 and L-selectin, and home to lymph nodes

10、. u limited capacity to perform effector functions when they encounter antigenu generate many effector cells upon antigen challenge u Effector memory T cellsu do not express CCR7 or L-selectin, and home to peripheral tissues, u especially mucosa. u produce effector cytokines upon antigenic stimulati

11、on u do not proliferate much. Based on their homing properties and effector functions. Subsets of memory T cells Nature Immunol, 2021, June, the reviews of memory T cellCD4+CD8+CD4+. Effector T cell subsets Th1-Th2 hypothesis 1986 Coffman and Mossman Th17 2005 Tfh 2000Discovery of CD4+ Th cell subse

12、ts How they are induced, What cytokines they produce What effector mechanisms they activate Th0Th1Th2Th17Humoral ImmunityImmune modulationThe subsets of CD4+Th cellsProperties of CD4+ Th1 and Th2 subsetsq Cytokines Stimuli that influence the pattern of Th cell differentiationq TCR signal strengthq D

13、ifferent subsets of dendritic cells may existq The genetic makeup of the host STAT: Signal transducer and activator of transcription Differentiation of Th1 Subsetv Stimulated by intracellular microbes that infect or activate macrophages or v NK cellsv Listeria, mycobacteria and Leishmaniav Important

14、 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 STAT1The molecular basis of Th1 differentiationThe interplay of signals from the T cell receptor, the cytokines IFN- and IL-1

15、2, 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- Differentiation of Th2 Subsetv Important TF for the Th2 differentiationv Stimulated by microbes and antigens that cause persistent or v repeated T cell stimu

16、lation with little inflammation or macrophage v activationv Helminth and allergensv Important cytokines for the Th2 differentiation IL-4 GATA-3: master regulator STAT6The molecular basis of Th2 differentiationThe interplay of signals from the T cell receptor, the cytokine IL-4, and the TF GATA-3 and

17、 STAT6Th2 differentiation is most dependent on IL-4 IL-4 STAT-6 Ag recognition by TCR GATA-3Development of Th1 and Th2 subsetsTh2 cell differentiation requires both GATA3 expression and STAT5 activationNature Review Immunol, 2021Differentiation of Th17 Subsetv Stimulated by zymosan, fungus, myobacte

18、riav Important cytokines for the Th17 differentiationv Important transcription factors (TF) for the Th17 differentiation IL-6 TGF- IL-23 IL-21 ROR-t: master regulator ROR- STAT3 AhRSteps in the differentiation of Th17 cellsConventional Th17 cell developmentImmunologic Review , 2021Follicular helper

19、T cells (TFH) Preferentially resident in B cell follicles Express CXCR5, a early defining marker 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

20、high-affinity isotype switched antibodies and B cell memoryAnatomical localization and cellular requirements for Tfh cell generationJEM, 2021JEM, 2021Anatomical localization and cellular requirements for Tfh cell generationCD4+CD25+ Regulatory T cells (Treg cells) A subset of CD4+ CD25+ T cells expr

21、essing Foxp3 Naturally present in immune system, constitute 5-10% of peripheral CD4+ T cells Suppress immune responses and maintain self-tolerance n Sakaguchi et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechani

22、sm of self-tolerance causes various autoimmune diseases. J Immunol 1995The Discovery of CD4+CD25+ Treg cellsIdentify CD25 as a surface markerThe discovery of Foxp3 and its role in CD4+CD25+ Tregn Hori et al. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003n Fo

23、ntenot et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol 2003n R. Khattri, et al, An essential role for Scurfin in CD4+CD25+ T regulatory cells, nNat. Immunol. 4 (2003), pp. 337342.r Natural Treg cells (nTreg) r Thymic derived, r highly controlled by

24、thymic microenvironmentr Induced Treg cells (iTreg) r Peripherally generated from Foxp3-CD4+T cellsr differentiated under more varied conditionsSubsets of Treg cells Thymic and Peripheral Generation of Foxp3+ Treg Cellsl TCRl Co-stimulationl Cytokine-mediated signalsMechanisms of iTreg cells differe

25、ntiationq TCRq TGF-q IL-2l Nonregulatory nave conventional CD4+T cells are able to acquire Foxp3 expression and regulatory function. l The conversion can occur in both in vitro and in vivol Treg cells converted in vivo can be functionally quite effectiveSubsets “in the makingTh9Th22Th9u Veldhoen, M.

26、 et al. Transforming growth factor- reprograms the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 13411346 (2021). uTh2 cells can change into an IL-9-producing T cell typeu Nowak, E.C. et al. IL-9 as a mediator of Th17-driven inflammatory disease

27、. J. Exp. Med. 206, 16531660 (2021). u Elyaman, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl. Acad. Sci. USA 106, 1288512890 (2021). u Beriou et al. TGF-beta induces IL-9 from human Th17 cells. J Immunol. 2021 Duhen, et a

28、l. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nature Immunol. 10, 857863 (2021). Trifari, et al. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells.

29、Nature Immunol. 10, 864871 (2021).Th22 In human, but not mouse Express IL-22 but not IL-17 or ROR-t May present a skin-homing subset responsible for skin inflammation such as psoriasisJEM, 2021CD4+ T cell flexibilityA possible hierarchy of stabilityTGF and IL-6 gradients regulate early Th17, iTreg,

30、and Th22 commitmentr The flexibility of T cell subsets?r What are the environmental (extrinsic) factors that r allow for plasticity?r What regulates lineage commitment versus flexibility?r Why do we need so many functional subsets?Questions?Innate T cells T cells express a limited number of TCRs abu

31、ndant 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 restricted. may bind to conserved ligands whose expression is triggered by ce

32、ll 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. Six of the best T cell functions Nature Review Immunol, 2021u Martin B et al. IL-17-Producing T cells Selectively Expand in Response to Pathog