细胞免疫T细胞活化的分子机制课件.ppt

1、整理ppt1T细胞活化机制细胞活化机制整理ppt2q Nave T cells Mature T cells that have not previously encountered antigen;Preferential migration to secondary lymphoid organs(lymph nodes),where they recognize antigenq Effector T cells Activated T cells capable of performing the functions required to eliminate foreign anti

2、gens Preferential migration to sites of infection or inflammation Short-livedq Memory T cells Long-lived,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 a

3、ctivation.整理ppt3应答诱导应答诱导外周淋巴器官内外周淋巴器官内抗原识别抗原识别T T细胞扩增和分化细胞扩增和分化分化的细胞分化的细胞进入循环进入循环效应效应T T细胞和其他白细细胞和其他白细胞迁移到感染部位胞迁移到感染部位在在外周外周效应效应T T细胞细胞遭遇抗原遭遇抗原效应效应T T细胞活化细胞活化T T细胞的效应功能细胞的效应功能整理ppt4.Activation of T cells changes the expression of several cell-surface molecules整理ppt5Functional responses of T cellsq S

4、ecretion of cytokinesq Proliferationq Differentiation into effector T cellsq Differentiation into memory T cells整理ppt6Secretion of cytokinesq One of the earliest detectable responses of T cells to antigen recognition q Principle cytokine:IL-2q Distinct sets of cytokines secreted by effector T cells整

5、理ppt7Clonal expansion of T cells整理ppt8Antigen-presenting cells are required for T cell activation整理ppt9q Specific antigen recognition by the T cells;q Stable adhesion of the T cells to the APCs;q Transduction of activating signals to the T cells.The initiation of T cell responses to specific antigen

6、 requires Each of these events is mediated by distinct sets of molecules on the T cells.整理ppt10T cell receptors and accessory molecules整理ppt11T cell receptor(TCR)The definitive T cell lineage marker q Recognition of MHC-associated peptide antigen Dual specificity MHC restriction Antigen specificityr

7、 No signal-transducing functions整理ppt12TCR complexComposed of TCR and CD3 protein 整理ppt13q invariant protein,identical in all T cells regardless of specificityq responsible for signaling,but not antigen recognitionImmunoreceptor tyrosine-based activation motif（ITAM)CD3 Contains two copies of a conse

8、rved sequence:tyrosine-X-X-leucine/isoleucine Important for signal transduction in T cells整理ppt14Antigen recognition and signaling functions of T cells Antigen recognition Signaling functions 整理ppt15Co-receptorsCD4 and CD8q Mature T cells express either CD4 or CD8,but not bothq Involved in MHC-restr

9、icted T cell activation CD4 Class MHC molecules CD8 Class MHC molecules A category of membrane proteins that enhance TCR signaling through simultaneous binding of the MHC molecules 整理ppt16整理ppt17Two-signal Hypothesis整理ppt18Signal 1TCR-MHC+Ag interaction not enough for full activation整理ppt19Overview

10、of TCR signallingNature Review Immunol 2013three major signalling pathways整理ppt20Provided by Costimulatory Molecules on activated APCsAPCT CellB7CD28Signal 2B7.1(CD80)B7.2(CD86)promote the survival and expansion of the T cells整理ppt21A comparison between signalling pathways in fully stimulated and in

11、 anergized T cellsdefects at various points in the MAPK(mitogen-activated protein kinase)pathway downstream of co-stimulationFathman and Lineberry,2007,Nature Immunology整理ppt22Functions of co-stimulators in T cell activationCyclosporin AFK506Rapamycin整理ppt23High-affinity IL-2 receptors are three-cha

12、in structures that are present only on activated T cells整理ppt24Mediated primarily by an autocrine growth pathway Proliferation整理ppt25Clonal expansionThe frequency of nave T cells specific for a given antigen is 1:105-6Ag-specific CD8+T cells 1:10 Ag-specific CD4+T cells 1:100/1000Ag-specific memory

13、T cells 1:104Ag is eliminated整理ppt26Phases of T cell responsespriming整理ppt27整理ppt28Variation in signal 3 causes naive CD4 T cells to acquire several distinct types of effector functions整理ppt29A model for the regulation of early TH2 differentiation by TCR signal strengthHidehiro Yamane&William E Paul

14、,2012 Nature Immunology整理ppt30A model for early determination of iTreg fate versus TH17 fate controlled by TCR signal strengthHidehiro Yamane&William E Paul,2012 Nature Immunology整理ppt31A model for early determination of Teff cell fate versus Tfh cell fate controlled by TCR signal strengthHidehiro Y

15、amane&William E Paul,2012 Nature Immunology整理ppt32Co-signaling receptors q CD28q ICOSq CTLA-4q PD-1q CD40Lq OX40LMembrane proteins expressed on T cells participate in responses to antigen by recognizing co-stimulators or co-inhibitors on APCs,but not recognizing antigenThe Ig superfamilyTNF receptor

16、 superfamily整理ppt33CD28q The discovery of CD28 as a prototype co-stimulatory TCR provided evidence for the two-signal model of T cell activation,q First identified co-stimulatory receptor to recognize B7 molecules on APCsq Principal receptor for delivering second signals for T cell activation整理ppt34

17、B7 moleculesBest-defined co-stimulatorsq Include B7.1(CD80)and B7.2(CD86)q Expressed mainly on APCs q Increased by microbial products and cytokinesq Important for the activation of nave T cells by interacting with CD28 on T cells整理ppt35ICOS(Inducible co-stimulator)q Expressed on activated T cells q

18、Binds ICOSL(ICOS ligand or B7-H2)q Important for the activation of effector cells to secrete some cytokines,such as IL-4 and IFN-q particularly important fro enabling CD4 T cells to helper cells for B-cell responses such as isotype switching 整理ppt36CTLA-4q Expressed on recently activated T cells q c

19、ompete with CD28 for the ligands CD80 and CD86 (with 20X higher affinity)q Acts as a signal dampener during the early stages of activation of nave and memory T cells(24-48 hr after antigen presentation)r Play a central role in self-tolerance整理ppt37Mechanisms of action of the inhibitory receptor CTLA

20、-4Competitively bind to B7Generate inhibitory signal整理ppt38For the discovery and development of a monoclonal antibody therapy that unleashes the immune system to combat cancer.科学很有意思，但同时也很艰辛。我认为现在让年轻科学家们去研究转化科学，做一些很快能应用到临床上的研究，会给他们施加过多压力。他们应该做的事情，是在基础生物学领域提出一些重要问题，并时不时地思考一下它们是怎样影响人体健康的，而不要把所有时间都花费在试

21、图“解决健康问题”上。我认为，真正好的基础研究始终能占据一席之地。整理ppt39PD-1(Programmed death-1)q Expressed on activated T cells as well as B cells and NK cellsq Its ligands PD-L1 and PD-L2 expressed by inflammatory tissues and cancer cells.q Inhibite chronically activated cells and responses in peripheral,non-lymphoid tissues 整理p

22、pt40The B7-CD28 families of co-stimulators and co-inhibitory receptors整理ppt41CD40Lr Member of TNF superfamily r Expressed on activated T cells r Binds to CD40 expressed on APCsr Indirecly amplify T cell responses by enhancing the expression of B7 molecules in APCs 整理ppt42Role of CD40 in T cell activ

23、ation.整理ppt43Lieping Chen and Dallas B.Flies,2013 Nature Immunology Review整理ppt44Co stimulatory and co inhibitory signalling pathways downstream of CD28 family receptors.Lieping Chen and Dallas B.Flies,2013 Nature Immunology Review整理ppt45The several levels of regulation in T cell co-signalingr Spati

24、otemporal regulation of co-signalingr Differential interactions through multiple interfaces.整理ppt46重大疾病免疫治疗的时代已经来临重大疾病免疫治疗的时代已经来临Science：重大疾病：重大疾病免疫疗法免疫疗法是是2013年年最最值得关注值得关注的六的六大科学领域大科学领域之一之一免疫细胞治疗展现惊人疗效，权威期刊的纷纷评述免疫治疗的成就整理ppt47Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle癌细胞抗原的释放 癌抗

25、原的提呈 肿瘤抗原特异性T细胞的 致敏与活化T细胞迁移到肿瘤T细胞的肿瘤局部浸润T细胞识别癌细胞杀伤癌细胞整理ppt48第二代抗体之一：抗肿瘤单克隆抗体第二代抗体之一：抗肿瘤单克隆抗体(CTLA-4 mAb)整理ppt49整理ppt50第二代抗体之二：抗肿瘤单克隆抗体第二代抗体之二：抗肿瘤单克隆抗体(PD-1/PD-L1 mAb)Anti-PD-1 mAbAnti-PD-L1 mAb整理ppt51The activation of CD8+T cellsq Require both antigen recognition and second signalsq May require seco

26、nd signal provided by CD4 Th cells in the conditions that tend to elicit weak innate immune reactions latent viral infection organ transplants tumor 整理ppt52Role of co-stimulation and helper T cells in the CD8+T cell differentiation整理ppt53Hierarchical T cell exhaustion during chronic infection整理ppt54

27、Subsets of exhausted T cells and combinatorial strategies to reverse exhaustion整理ppt55n Acuto O,VD Bartolo,and F Michel.Tailoring T-cell receptor signals by proximal negative feedback mechanisms.Nature Reviews Immunology 8:699-712,2008.n Chen L.Co-inhibitory molecules of the B7-CD28 family in the co

28、ntrol of T-cell immunity.Nature Reviews Immunology 4:336-347,2004.n Greenwald RJ,GJ Freeman,and AH Sharpe.The B7 family revisited.Annual Review of Immunology 23:515-548,2005.n Huse M,EJ Quann,and MM Davis.Shouts,whispers and the kiss of death:directional secretion in T cells.Nature Immunology 9:1105

29、-1111,2008.n Seder RA,and R Ahmed.Similarities and differences in CD4+and CD8+effector and memory T cell generation.Nature Immunology 4:835-842,2003 n Chen L and Flies DB.Molecular mechanisms of T cell co-stimulation and co-inhibition.Nature Reviews Immunology 12:227-242,2013n Wherry,E.J.T cell exhaustion.Nature Immunol.12,492499(2011).n Williams MA,and MJ Bevan.Effector and memory CTL differentiation.Annual Review of Immunology 25:171-192,2007.Selected readings