T cell激活

TcellactivationCHAPTERNINETopicsinChapterNine1.Generalprinciplesofsignaltransduction2.ThesignalofantigenrecognitionandthesignaltransductioninTcells3.ThesecondsignalforTactivation.Theproductsexpressionoftheactivatedgenes4.Cytokinereceptor-initiatedsignalinginTactivation5.DifferentiationoffunctionalTsubset6.MemoryTcells7.ActivationofTcellsbysuperantigensAseriesofeventstakeplaceinTcellsafterantigenrecognition:signaltransductionthroughcellmembrane,activationandtrans-locationofnuclearfactorsincytosol,transcriptionactivationofgenesinnucleus,synthesisandexpressionofnewmolecules,secretingofcytokines,initiationofcelldivisioncycle,differentiationofcellsubsets,formationofimmunologicalmemory,etc.GeneralprinciplesofsignaltransductionchapternineTCellActivation1ProteinphosphorylationanddephosphorylationarecatalyzedbyproteinkinaseandphosphataserespectivelyProteinATP-OH+ADP+ProteinO‖-O-P-O-|O-ProteinO‖-O-P-O-|O-Protein-OH++O‖HO-O-P-O-|O-H2O蛋白激酶蛋白磷酸酶蛋白磷酸化蛋白脱磷酸化a蛋白激酶和蛋白磷酸酶ProteinkinasesandproteinphosphatasesinTactivationproteintyrosineSrcfamily:Lck,Fyn,Lyn,Blkkinase(PTK)Sykfamily:ZAP-70,SykJakfamily:Jak1,Jak2,Jak3Proteinkinaseproteinserine/ProteinkinaseC(PKC)threoninekinaseMAPK(mitogen-activationproteinkinase)PI3kinase(PI:phosphatylinositide)ProteinTyrosineCD45Proteinphosphatase(PTP)SHP(SH2-containingphosphatase)phosphataseSHIP(SH2-containinginositalpoly-phosphate5-phosphatase)Serine/threoninephosphataseCalcineurin钙调磷酸酶蛋白激酶蛋白磷酸酶蛋白酪氨酸激酶蛋白酪氨酸磷酸酶蛋白激酶Ｃ蛋白丝/苏氨酸激酶蛋白丝/苏氨酸磷酸酶SrcCskJakSykBtkPI3-kSH3SH2SH1(catalysisdomain)pTheproteinkinasefamiliesinvolvedinsignaltransductionforTandBcellactivationp85p110KYmATPYlysinetyrosinetyrosine271394505SH3SH2SH1ThemolecularstructureofthePTKSrcfamilyCNITAM：…D/ExxYxxL/Vx(7-11)YxxL/V…YLxxSH2结构域ITAMSHCLYPTKppxxT细胞激活中ITAM的基本结构及其磷酸化后对SHC的招募作用方框上方为ITAM的基本结构。其中的酪氨酸（Y）可以在PTK的作用下发生磷酸化。发生磷酸化的酪氨酸（pY)可以通过与SH2结构域的结合，使SH2携带蛋白（SHC)被募集到带有ITAM基序的跨模分子所在的胞膜内测。B细胞和T细胞抗原识别受体及相关分子的比较CD81(TAPA-1)CD19YAgC3dCD21(CR2)Ig/IgBCRTCRMHCCD4BlkZAP-70LckFynLynSyk抗原肽APCT细胞B细胞CD45CD45－带有调控结构域而不显示酶活性；－可有细胞膜整合蛋白和胞浆蛋白两种形式；－为大分子复合物的形成提供支架；－参与细胞活化中胞内信号的整合与传递。衔接蛋白的主要特点和功能衔接蛋白（adaptor）是信号转导中的信号分子，参与蛋白与蛋白间的反应。衔接蛋白可带有酪氨酸残基，被PTK活化。T细胞活化连接蛋白(linkerforactivationofTcell,LAT):含SH2的白细胞磷酸化蛋白(SH2-containingleukocytephospho-protein,SLP-76);生长因子受体结合蛋白(growthfactorreceptor-bindingprotein,Grb-2）AdapterproteinsinTcellactivationaTMPRSH2SH2SH3SH3YYYYYYYYYYYYLATSLP-76Grb-2TyrosineresidueThesignalofantigenrecognitionandthesignaltransductioninTcellchapternineTCellActivation2免疫突触的形成使多个TCR-pMHC三元体聚集成簇CD4LFA-1TCRCD28CD2cSMACpSMACABC脂筏APCT细胞ICAM-1MHCB7LFA-3CentralorPeripheralSupra-MolecularActivationCluster信号的跨膜传递和转导通路的启动FormationofImmunologicalSynapseMultimerization(多聚作用)ofthemembranemoleculesinrelationtotheTCR-pMHCcomplexviasynapseformationAPCAPCAPCAPCLFA-1peptideTCRMHCICAM-1TMHCTCRPeptideT途径APKC钙调磷酸酶MAP激酶PIP2IP3Ras-GDPRas-GTPDAGCa2+RafPLC-SosGSK3NF-ATNF-AT-pc-Junc-FosB7CD28PI3kITAMpY胞核LckFynpMHCTCRCD4ITAMYpGrb-2LATSLP-76ZAP-70pYpYpYpY途径B途径CAKTPTP结构域pCD45I-BNF-BNF-Bp52p65p52p65NF-ATOCTNF-BAP-1NF-ATOCTIL-2genep52p65PLCGadsNCKPAK1RHO肌动蛋白细胞骨架重排Y505免疫突触YpYpYpAP-1T细胞激活的信号转导KYmATPYlysinetyrosinetyrosine271394505PKYmPATPYActivationofSrc-PTKbytransphosphorylationofthetyrosine394inSH1domainbetweenSrcmoleculesSH3SH2SH1蛋白酪氨酸磷酸酶CD45参与SrcPTK的激活NYYP505505YYYY相互磷酸化PATPATPPCD45PTPYY505394CCskPTKPSrcPTK激活SrcCskJakSykBtkSH3SH2SH1p途径APKC钙调磷酸酶MAP激酶PIP2IP3Ras-GDPRas-GTPDAGCa2+RafPLC-SosGSK3NF-ATNF-AT-pc-Junc-FosB7CD28PI3kITAMpY胞核LckFynpMHCTCRCD4ITAMYpGrb-2LATSLP-76ZAP-70pYpYpYpY途径B途径CAKTPTP结构域pCD45I-BNF-BNF-Bp52p65p52p65NF-ATOCTNF-BAP-1NF-ATOCTIL-2genep52p65PLCGadsNCKPAK1RHO肌动蛋白细胞骨架重排Y505免疫突触YpYpYpAP-1T细胞激活的信号转导B细胞和T细胞抗原识别受体及相关分子的比较CD81(TAPA-1)CD19YAgC3dCD21(CR2)Ig/IgBCRTCRMHCCD4BlkZAP-70LckFynLynSyk抗原肽APCT细胞B细胞CD45CD45Srcfamily:Lck,Fyn,Lyn,BlkTyrosinekinaseSykfamily:ZAP-70,SykJakfamily:Jak1,Jak2,Jak3ProteinkinaseProteinkinaseC(PKC)Serine/threonineMAPkinase(MAP:mitogen-activationkinaseprotein)PI3kinase(PI:phosphatylinositide)CD45Tyrosinephos-SHP(SH2-containingphosphatase)phataseSHIP(SH2-containinginositalpoly-Proteinphosphate5-phosphatase)phosphataseSerine/threonineCalcineurin钙调磷酸酶phosphataseProteinkinasesandproteinphosphatasesinTactivation蛋白激酶蛋白磷酸酶蛋白酪氨酸激酶蛋白酪氨酸磷酸酶蛋白激酶Ｃ蛋白丝/苏氨酸激酶SH3SH2SH1(catalysisdomain)pp85p110SrcCskJakSykBtkPI3-k途径APKC钙调磷酸酶MAP激酶PIP2IP3Ras-GDPRas-GTPDAGCa2+RafPLC-SosGSK3NF-ATNF-AT-pc-Junc-FosB7CD28PI3kITAMpY胞核LckFynpMHCTCRCD4ITAMYpGrb-2LATSLP-76ZAP-70pYpYpYpY途径B途径CAKTPTP结构域pCD45I-BNF-BNF-Bp52p65p52p65NF-ATOCTNF-BAP-1NF-ATOCTIL-2genep52p65PLCGadsNCKPAK1RHO肌动蛋白细胞骨架重排Y505免疫突触YpYpYpAP-1T细胞激活的信号转导T细胞抗原激活信号转导磷脂酰肌醇途径的启动三磷酸肌醇（IP3）Inositol1,4,5-trisphosphate二磷酸磷脂酰肌醇（PIP2）Phosphalidylinositol4,5-bisphosphate磷脂酶C（PLC-）二酰甘油（DAG）1,2-Diacylglycerol胞质Srcfamily:Lck,Fyn,Lyn,BlkTyrosinekinaseSykfamily:ZAP-70,SykJakfamily:Jak1,Jak2,Jak3ProteinkinaseProteinkinaseC(PKC)Serine/threonineMAPkinase(MAP:mitogen-activationkinaseprotein)PI3kinase(PI:phosphatylinositide)CD45Tyrosinephos-SHP(SH2-containingphosphatase)phataseSHIP(SH2-containin