细胞免疫T细胞活化的分子机制ppt课件.ppt

T细胞活化机制 1 Na veTcellsMatureTcellsthathavenotpreviouslyencounteredantigen Preferentialmigrationtosecondarylymphoidorgans lymphnodes wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort livedMemoryTcellsLong lived functionallysilentcells MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous centralandeffector BasedonthehistoryofantigenencounterandthestageofTcellactivation 2 应答诱导 外周淋巴器官内抗原识别 T细胞扩增和分化 分化的细胞进入循环 效应T细胞和其他白细胞迁移到感染部位 在外周效应T细胞遭遇抗原 效应T细胞活化 T细胞的效应功能 3 ActivationofTcellschangestheexpressionofseveralcell surfacemolecules 4 FunctionalresponsesofTcells SecretionofcytokinesProliferationDifferentiationintoeffectorTcellsDifferentiationintomemoryTcells 5 Secretionofcytokines OneoftheearliestdetectableresponsesofTcellstoantigenrecognitionPrinciplecytokine IL 2DistinctsetsofcytokinessecretedbyeffectorTcells 6 ClonalexpansionofTcells 7 Antigen presentingcellsarerequiredforTcellactivation 8 SpecificantigenrecognitionbytheTcells StableadhesionoftheTcellstotheAPCs TransductionofactivatingsignalstotheTcells TheinitiationofTcellresponsestospecificantigenrequires EachoftheseeventsismediatedbydistinctsetsofmoleculesontheTcells 9 Tcellreceptorsandaccessorymolecules 10 Tcellreceptor TCR ThedefinitiveTcelllineagemarkerRecognitionofMHC associatedpeptideantigenDualspecificityMHCrestrictionAntigenspecificityNosignal transducingfunctions 11 TCRcomplex ComposedofTCRandCD3protein 12 invariantprotein identicalinallTcellsregardlessofspecificityresponsibleforsignaling butnotantigenrecognition Immunoreceptortyrosine basedactivationmotif ITAM CD3 Containstwocopiesofaconservedsequence tyrosine X X leucine isoleucineImportantforsignaltransductioninTcells 13 AntigenrecognitionandsignalingfunctionsofTcells AntigenrecognitionSignalingfunctions 14 Co receptors CD4andCD8Mature TcellsexpresseitherCD4orCD8 butnotbothInvolvedinMHC restrictedTcellactivationCD4Class MHCmoleculesCD8Class MHCmolecules AcategoryofmembraneproteinsthatenhanceTCRsignalingthroughsimultaneousbindingoftheMHCmolecules 15 16 Two signalHypothesis 17 Signal1 TCR MHC Aginteractionnotenoughforfullactivation 18 OverviewofTCRsignalling NatureReviewImmunol2013 threemajorsignallingpathways 19 ProvidedbyCostimulatoryMoleculesonactivatedAPCs Signal2 B7 1 CD80 B7 2 CD86 promotethesurvivalandexpansionoftheTcells 20 AcomparisonbetweensignallingpathwaysinfullystimulatedandinanergizedTcells defectsatvariouspointsintheMAPK mitogen activatedproteinkinase pathwaydownstreamofco stimulation FathmanandLineberry 2007 NatureImmunology 21 Functionsofco stimulatorsinTcellactivation CyclosporinAFK506Rapamycin 22 High affinityIL 2receptorsarethree chainstructuresthatarepresentonlyonactivatedTcells 23 Mediatedprimarilybyanautocrinegrowthpathway Proliferation 24 Clonalexpansion Thefrequencyofna veTcellsspecificforagivenantigenis 1 105 6 Ag specificCD8 Tcells1 10Ag specificCD4 Tcells1 100 1000 Ag specificmemoryTcells1 104 Agiseliminated 25 PhasesofTcellresponses priming 26 27 Variationinsignal3causesnaiveCD4Tcellstoacquireseveraldistincttypesofeffectorfunctions 28 AmodelfortheregulationofearlyTH2differentiationbyTCRsignalstrength HidehiroYamane WilliamEPaul 2012NatureImmunology 29 AmodelforearlydeterminationofiTregfateversusTH17fatecontrolledbyTCRsignalstrength HidehiroYamane WilliamEPaul 2012NatureImmunology 30 AmodelforearlydeterminationofTeffcellfateversusTfhcellfatecontrolledbyTCRsignalstrength HidehiroYamane WilliamEPaul 2012NatureImmunology 31 Co signalingreceptors CD28ICOSCTLA 4PD 1CD40LOX40L MembraneproteinsexpressedonTcellsparticipateinresponsestoantigenbyrecognizingco stimulatorsorco inhibitorsonAPCs butnotrecognizingantigen TheIgsuperfamily TNFreceptorsuperfamily 32 CD28 ThediscoveryofCD28asaprototypeco stimulatoryTCRprovidedevidenceforthetwo signalmodelofTcellactivation Firstidentifiedco stimulatoryreceptortorecognizeB7moleculesonAPCsPrincipalreceptorfordeliveringsecondsignalsforTcellactivation 33 B7molecules Best definedco stimulatorsIncludeB7 1 CD80 andB7 2 CD86 ExpressedmainlyonAPCsIncreasedbymicrobialproductsandcytokinesImportantfortheactivationofna veTcellsbyinteractingwithCD28onTcells 34 ICOS Inducibleco stimulator ExpressedonactivatedTcellsBindsICOSL ICOSligandorB7 H2 Importantfortheactivationofeffectorcellstosecretesomecytokines suchasIL 4andIFN particularlyimportantfroenablingCD4TcellstohelpercellsforB cellresponsessuchasisotypeswitching 35 CTLA 4 ExpressedonrecentlyactivatedTcellscompetewithCD28fortheligandsCD80andCD86 with20Xhigheraffinity Actsasasignaldampenerduringtheearlystagesofactivationofna veandmemoryTcells 24 48hrafterantigenpresentation Playacentralroleinself tolerance 36 MechanismsofactionoftheinhibitoryreceptorCTLA 4 CompetitivelybindtoB7 Generateinhibitorysignal 37 Forthediscoveryanddevelopmentofamonoclonalantibodytherapythatunleashestheimmunesystemtocombatcancer 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 38 PD 1 Programmeddeath 1 ExpressedonactivatedTcellsaswellasBcellsandNKcellsItsligandsPD L1andPD L2expressedbyinflammatorytissuesandcancercells Inhibitechronicallyactivatedcellsandresponsesinperipheral non lymphoidtissues 39 TheB7 CD28familiesofco stimulatorsandco inhibitoryreceptors 40 CD40L MemberofTNFsuperfamilyExpressedonactivatedTcellsBindstoCD40expressedonAPCsIndireclyamplifyTcellresponsesbyenhancingtheexpressionofB7moleculesinAPCs 41 RoleofCD40inTcellactivation 42 LiepingChenandDallasB Flies 2013NatureImmunologyReview 43 Co stimulatoryandco inhibitorysignallingpathwaysdownstreamofCD28familyreceptors LiepingChenandDallasB Flies 2013NatureImmunologyReview 44 TheseverallevelsofregulationinTcellco signaling Spatiotemporalregulationofco signalingDifferentialinteractionsthroughmultipleinterfaces 45 重大疾病免疫治疗的时代已经来临 Science 重大疾病免疫疗法是2013年最值得关注的六大科学领域之一 46 StimulatoryandInhibitoryFactorsintheCancer ImmunityCycle 癌细胞抗原的释放癌抗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 47 第二代抗体之一 抗肿瘤单克隆抗体 CTLA 4mAb 48 49 第二代抗体之二 抗肿瘤单克隆抗体 PD 1 PD L1mAb Anti PD 1mAb Anti PD L1mAb 50 TheactivationofCD8 Tcells RequirebothantigenrecognitionandsecondsignalsMayrequiresecondsignalprovidedbyCD4Thcellsintheconditionsthattendtoelicitweakinnateimmunereactionslatentviralinfectionorgantransplantstumor 51 Roleofco stimulationandhelperTcellsintheCD8 Tcelldifferentiation 52 HierarchicalTcellexhaustionduringchronicinfection 53 SubsetsofexhaustedTcellsandcombinatorialstrategiestoreverseexhaustion 54 AcutoO VDBartolo andFMichel TailoringT cellreceptorsignalsbyproximalnegativefeedbackmechanisms NatureReviewsImmunology8 6