细胞免疫T细胞活化的分子机制课件

T细胞活化机制细胞活化机制1整理pptq 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 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 effector)Based on the history of antigen encounter and the stage of T cell activation.2整理ppt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3整理ppt.Activation of T cells changes the expression of several cell-surface molecules4整理pptFunctional responses of T cellsq Secretion of cytokinesq Proliferationq Differentiation into effector T cellsq Differentiation into memory T cells5整理pptSecretion 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 cells6整理pptClonal expansion of T cells7整理pptAntigen-presenting cells are required for T cell activation8整理pptq 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 requires Each of these events is mediated by distinct sets of molecules on the T cells.9整理pptT cell receptors and accessory molecules10整理pptT cell receptor(TCR)The definitive T cell lineage marker q Recognition of MHC-associated peptide antigen Dual specificity MHC restriction Antigen specificityr No signal-transducing functions11整理pptTCR complexComposed of TCR and CD3 protein 12整理pptq 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 conserved sequence:tyrosine-X-X-leucine/isoleucine Important for signal transduction in T cells13整理pptAntigen recognition and signaling functions of T cells Antigen recognition Signaling functions 14整理pptCo-receptorsCD4 and CD8q Mature T cells express either CD4 or CD8,but not bothq Involved in MHC-restricted 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 15整理ppt16整理pptTwo-signal Hypothesis17整理pptSignal 1TCR-MHC+Ag interaction not enough for full activation18整理pptOverview of TCR signallingNature Review Immunol 2013three major signalling pathways19整理pptProvided by Costimulatory Molecules on activated APCsAPCT CellB7CD28Signal 2B7.1(CD80)B7.2(CD86)promote the survival and expansion of the T cells20整理pptA comparison between signalling pathways in fully stimulated and in anergized T cellsdefects at various points in the MAPK(mitogen-activated protein kinase)pathway downstream of co-stimulationFathman and Lineberry,2007,Nature Immunology21整理pptFunctions of co-stimulators in T cell activationCyclosporin AFK506Rapamycin22整理pptHigh-affinity IL-2 receptors are three-chain structures that are present only on activated T cells23整理pptMediated primarily by an autocrine growth pathway Proliferation24整理pptClonal 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 T cells 1:104Ag is eliminated25整理pptPhases of T cell responsespriming26整理ppt27整理pptVariation in signal 3 causes naive CD4 T cells to acquire several distinct types of effector functions28整理pptA model for the regulation of early TH2 differentiation by TCR signal strengthHidehiro Yamane&William E Paul,2012 Nature Immunology29整理pptA model for early determination of iTreg fate versus TH17 fate controlled by TCR signal strengthHidehiro Yamane&William E Paul,2012 Nature Immunology30整理pptA model for early determination of Teff cell fate versus Tfh cell fate controlled by TCR signal strengthHidehiro Yamane&William E Paul,2012 Nature Immunology31整理pptCo-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 superfamily32整理pptCD28q 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 activation33整理pptB7 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