T细胞进展TCR-MHC(2012)

T细胞识别抗原的分子基础一、TCR及其共受体二、MHC分子及其与抗原肽的相互作用三、MHC多聚体及其应用T细胞对抗原的识别是特异性免疫应答发生的先决条件•T细胞识别抗原的物质基础是其表面的TCR•TCR识别的配体是与MHC分子结合的抗原肽•TCR识别需要CD4/CD8分子作为共受体AntigenrecognitionbyTcellsrequirespeptideantigensandpresentingcellsthatexpressMHCmoleculesMHC分子提呈抗原肽供T细胞识别一、T细胞抗原受体（TCR）•结构•基因及多样性形成的机制•与抗原肽/MHC复合物的相互作用ThestructureoftheTcellreceptorStructureofTCRissimilartothatofFab图1Threesetsofkeyantigen-recognitionreceptorshavesimilaroverallanatomies图2•Domainstructure:Iggenesuperfamily•Monovalent•Noalternativeconstantregions•Neversecreted•Heterodimeric,chainsaredisuphide-bonded•Veryshortintracytoplasmictail•PositivelychargedaminoacidsintheTMregion•AntigencombiningsitemadeofjuxtaposedVaandVbregions•30,000identicalspecificityTcRpercellTheTcellantigenreceptor•TcRarehighlyvariableinanindividual•DiversityfocusesonsmallchangesintheshapepresentedattheendoftheTcellreceptor(CDR).•ThemechanismsresponsibleforvariabilityarecloselyrelatedtothedevelopmentalstagesofTcells•Themechanismsofdiversitygenerationaresimilartothoseusedintheimmunoglobulingeneswithrespectto:Geneorganisation,rearrangementandrandomjoiningerrorTcellantigenreceptordiversityGenerationofdiversityintheTcRCOMBINATORIALDIVERSITYMultiplegermlinesegmentsInthehumanTcRVariable(V)segments:~70,52Diversity(D)segments:0,2Joining(J)segments:61,13TheneedtopairandchainstoformabindingsitedoublesthepotentialfordiversityJUNCTIONALDIVERSITYAdditionofnon-templateencoded(N)andpalindromic(P)nucleotidesatimprecisejointsmadebetweenV-D-JelementsSOMATICMUTATIONISNOTUSEDTOGENERATEDIVERSITYINTcRTcROrganisationofTcRgenesL&Vx70-80CTcRD1J1x6C1D2J2x7C2TcRgenessegmentedintoV,(D),J&Celements(VARIABLE,DIVERSITY,JOINING&CONSTANT)CloselyresembleIggenes(~IgLand~IgH)ThisexampleshowsthemouseTcRlocusJx61L&Vx52TcRgenerearrangementbySOMATICRECOMBINATIONSplicedTcRmRNAGermlineTcRVnJCV2V1RearrangedTcR1°transcriptRearrangementverysimilartotheIgLchainsRearrangedTcR1°transcriptSplicedTcRmRNAL&Vx52D1JC1D2JC2GermlineTcRTcRgenerearrangementSOMATICRECOMBINATIOND-JJoiningV-DJjoiningC-VDJjoiningGenerationofdiversityintheTcRCOMBINATORIALDIVERSITYRandomrecombinationofmultiplegermlinesegmentsJUNCTIONALDIVERSITYReadingDregionin3framesAdditionofP&NnucleotidesNOSOMATICMUTATIONInTcRIfTcRdidundergosomaticmutation:TcRinteractswithentiretopsurfaceofMHC-peptideantigencomplexSomaticmutationintheTcRcouldmutateaminoacidsthatinteractwiththeMHCmoleculecausingacompletelossofpeptide-MHCrecognitionTcellreceptor-and-chaingenerearrangementandexpressionElementImmunoglobulinTcRVariablesegmentsDiversitysegmentsDsegmentsinall3framesJoiningsegmentsJointswithN&PnucleotidesNo.ofVgenepairsJunctionaldiversityTotaldiversityH51~30Rare5235193640~1013~1013~1016**~1016690-5(1)*52~7020Often-136121*OnlyhalfofhumanchainshaveN&Pregions**NoofdistinctreceptorsincreasedfurtherbysomaticmutationEstimateofthenumberofhumanTcRandIgV(D)JrearrangementsduringTcelldevelopment-chainfirst,then-chainV(D)JrearrangementsduringTcelldevelopment-chainfirst,then-chainTheoutlinestructuresoftheCD4andCD8co-receptormoleculesCoreceptorinteractions•CD4:monomer,4IgSFdomains,bindingMHCII.•CD8:2chainswithsingleIgSFdomain,CD8:conventionalMHCICD8:nonclassicalMHCI•TheCD8-MHCinteractionhasaKoffatleast2ordersofmagnitudefasterthanTCR-pMHCinteractions,andtheCD4-MHCinteractionseemstobemuchlessstable.•CoreceptorsbindtothesameMHCmoleculeengagedbytheTCR,andassociatewiththeTCRviathesignalingmoleculesp56lckandZAP-70.ThebindingsitesforCD4andCD8onMHClieintheIg-likedomains•AntigenrecognitionleadstoweakphosphorylationoftheTCR•Thecombinedavidityof2-siteinteractionsinvolvingcoreceptorbindingtotheectodomainoftheMHCmoleculeandtointracellularcomponentsoftheTCR(viaCD4-p56lckSH2domaininteractswithphosphorylatedITAMofCD3orZAP-70associatedwithTCR),issufficienttorecruitcoreceptorandp56lcktothetriggeredTCR-pMHCcomplex.•Stablyrecruitedp56lckthenisexpectedtoamplifytheinitialphosphorylationsignal.•ThesignalamplificationremainsentirelysubservienttoagonisticTCRsignaling.Apossiblescenarioforco-receptorinteractionCoreceptorinteractionsandstructurehierarchicalaffinitydifferencesinTCR-pMHCandcoreceptor-MHCcomplexesensuretheseeventsoccursequentially.TheTcellreceptorbindstotheMHC:peptidecomplex二、MHC分子（一）MHC-I类和-II类分子（二）MHC生物学功能ThegeneticorganizationoftheMHCinhumanandthemouse（一）经典的HLA-I类和-II类抗原1．HLA-I类分子结构*由链（重链）和链（轻链）组成的异源二聚体，其中重链由HLA-I类基因编码且为跨膜链，具有多态性。*可分为4个区(1)肽结合区：结合抗原肽，多态性区域(2)Ig样区：与CD8分子结合的部位(3)跨膜区：将HLA分子锚定在胞膜上(4)胞浆区：与信息转导有关ThestructureofanMHCclassImolecules(determinedbyX-raycrystallography)MHC-I类分子结构α链：43KDaβ链：12KDa2.HLA-II类分子的结构*由链和链组成的异源二聚体，链和链均由HLA-II类基因编码且均为跨膜链，均具有多态性。*可分为4个区(1)肽结合区：结合抗原肽，多态性区域(2)Ig样区：与CD4分子结合的部位(3)跨膜区：将HLA分子锚定在胞膜上(4)胞浆区：与信息转导有关ThestructureofanMHCclassIImolecules(resembleMHCclassImoleculesinstructure)MHC-II类分子结构α链：34KDaβ链：29KDa（二）MHC生物学功能及其分子机制1、MHC分子的生物学功能抗原提呈MHC分子的抗原结合凹槽选择性结合抗原肽→形成MHC分子-抗原肽复合物→以MHC限制性的方式供T细胞识别→启动特异性免疫应答。*CD4+T细胞识别抗原肽/MHC-II复合物*CD8+T细胞识别抗原肽/MHC-I复合物MHC分子提呈抗原肽供T细胞识别TCR识别抗原肽的MHC限制性2、MHC分子与抗原肽的相互作用（1）抗原肽和MHC分子相互作用的分子基础MHC分子方面*MHC的多态