細胞免疫T細胞活化的分子機制課件

T細胞活化機制整理ppt1T細胞活化機制整理ppt1Na?veTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.整理ppt2Na?veTcellsBasedonthehis應(yīng)答誘導(dǎo)外周淋巴器官內(nèi)抗原識別T細胞擴增和分化分化的細胞進入循環(huán)效應(yīng)T細胞和其他白細胞遷移到感染部位在外周效應(yīng)T細胞遭遇抗原效應(yīng)T細胞活化T細胞的效應(yīng)功能整理ppt3應(yīng)答誘導(dǎo)外周淋巴器官內(nèi)T細胞擴增和分化分化的細胞效應(yīng)T細胞和.ActivationofTcellschangestheexpressionofseveralcell-surfacemolecules整理ppt4.ActivationofTcellschangesFunctionalresponsesofTcellsSecretionofcytokinesProliferationDifferentiationintoeffectorTcellsDifferentiationintomemoryTcells整理ppt5FunctionalresponsesofTcellSecretionofcytokinesOneoftheearliestdetectableresponsesofTcellstoantigenrecognitionPrinciplecytokine:IL-2DistinctsetsofcytokinessecretedbyeffectorTcells整理ppt6SecretionofcytokinesOneofClonalexpansionofTcells整理ppt7ClonalexpansionofTcells整理pAntigen-presentingcellsarerequiredforTcellactivation整理ppt8Antigen-presentingcellsarerSpecificantigenrecognitionbytheTcells;StableadhesionoftheTcellstotheAPCs;TransductionofactivatingsignalstotheTcells.TheinitiationofTcellresponsestospecificantigenrequiresEachoftheseeventsismediatedbydistinctsetsofmoleculesontheTcells.

整理ppt9SpecificantigenrecognitionTcellreceptorsandaccessorymolecules整理ppt10TcellreceptorsandaccessoryTcellreceptor(TCR)ThedefinitiveTcelllineagemarker

RecognitionofMHC-associatedpeptideantigen

DualspecificityMHCrestrictionAntigenspecificityNosignal-transducingfunctions整理ppt11Tcellreceptor(TCR)ThedefinTCRcomplexComposedofTCRandCD3

protein

整理ppt12TCRcomplexComposedofTCRandinvariantprotein,identicalinallTcellsregardlessofspecificityresponsibleforsignaling,butnotantigenrecognitionImmunoreceptortyrosine-basedactivationmotif

（ITAM)CD3Containstwocopiesofaconservedsequence:

tyrosine-X-X-leucine/isoleucineImportantforsignaltransductioninTcells整理ppt13invariantprotein,identicalAntigenrecognitionandsignalingfunctionsofTcellsAntigenrecognitionSignalingfunctions整理ppt14AntigenrecognitionandsignalCo-receptorsCD4andCD8MatureTcellsexpresseitherCD4orCD8,butnotbothInvolvedinMHC-restrictedTcellactivationCD4ClassⅡMHCmoleculesCD8ClassⅠMHCmoleculesAcategoryofmembraneproteinsthatenhanceTCRsignalingthroughsimultaneousbindingoftheMHCmolecules整理ppt15Co-receptorsCD4andCD8Acateg整理ppt16整理ppt16Two-signalHypothesis整理ppt17Two-signalHypothesis整理ppt17Signal1TCR-MHC+Aginteractionnotenoughforfullactivation整理ppt18Signal1TCR-MHC+AginteractiOverviewofTCRsignallingNatureReviewImmunol2013threemajorsignallingpathways整理ppt19OverviewofTCRsignallingNatuProvidedbyCostimulatoryMoleculesonactivatedAPCsAPCTCellB7CD28Signal2B7.1(CD80)B7.2(CD86)promotethesurvivalandexpansionoftheTcells整理ppt20ProvidedbyCostimulatoryMolAcomparisonbetweensignallingpathwaysinfullystimulatedandinanergizedTcellsdefectsatvariouspointsintheMAPK(mitogen-activatedproteinkinase)pathwaydownstreamofco-stimulationFathmanandLineberry,2007,NatureImmunology整理ppt21AcomparisonbetweensignallinFunctionsofco-stimulatorsinTcellactivationCyclosporinAFK506Rapamycin整理ppt22Functionsofco-stimulatorsinHigh-affinityIL-2receptorsarethree-chainstructuresthatarepresentonlyonactivatedTcells整理ppt23High-affinityIL-2receptorsaMediatedprimarilybyanautocrinegrowthpathwayProliferation整理ppt24MediatedprimarilybyanautocClonalexpansionThefrequencyofna?veTcellsspecificforagivenantigenis~1:105-6Ag-specificCD8+Tcells1:10

Ag-specificCD4+Tcells1:100/1000Ag-specificmemoryTcells1:104Agiseliminated整理ppt25ClonalexpansionThefrequencyPhasesofTcellresponsespriming整理ppt26PhasesofTcellresponsesprim整理ppt27整理ppt27Variationinsignal3causesnaiveCD4Tcellstoacquireseveraldistincttypesofeffectorfunctions整理ppt28Variationinsignal3causesnAmodelfortheregulationofearlyTH2differentiationbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology整理ppt29AmodelfortheregulationofAmodelforearlydeterminationofiTregfateversusTH17fatecontrolledbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology整理ppt30AmodelforearlydeterminatioAmodelforearlydeterminationofTeffcellfateversusTfhcellfatecontrolledbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology整理ppt31AmodelforearlydeterminatioCo-signalingreceptors

CD28ICOSCTLA-4PD-1CD40LOX40LMembraneproteinsexpressedonTcellsparticipateinresponsestoantigenbyrecognizingco-stimulators

orco-inhibitors

onAPCs,butnotrecognizingantigenTheIgsuperfamilyTNFreceptorsuperfamily整理ppt32Co-signalingreceptorsCD28MCD28ThediscoveryofCD28asaprototypeco-stimulatoryTCRprovidedevidenceforthetwo-signalmodelofTcellactivation,Firstidentifiedco-stimulatoryreceptortorecognizeB7moleculesonAPCsPrincipalreceptorfordeliveringsecondsignalsforTcellactivation整理ppt33CD28ThediscoveryofCD28asB7moleculesBest-definedco-stimulatorsIncludeB7.1(CD80)andB7.2(CD86)ExpressedmainlyonAPCs

IncreasedbymicrobialproductsandcytokinesImportantfortheactivationofna?veTcellsbyinteracting

with

CD28onTcells整理ppt34B7moleculesBest-definedco-stICOS(Inducibleco-stimulator)

ExpressedonactivatedTcellsBindsICOSL(ICOSligandorB7-H2)

Importantfortheactivationofeffectorcellstosecretesome

cytokines,suchasIL-4andIFN-

particularlyimportantfroenablingCD4TcellstohelpercellsforB-cellresponsessuchasisotypeswitching整理ppt35ICOS(Inducibleco-stimulator)CTLA-4ExpressedonrecentlyactivatedTcellscompetewithCD28fortheligandsCD80andCD86(with20Xhigheraffinity)

Actsasasignaldampenerduringtheearlystagesofactivationofna?veandmemoryTcells(24-48hrafterantigenpresentation)

Playacentralroleinself-tolerance整理ppt36CTLA-4ExpressedonrecentlyMechanismsofactionoftheinhibitoryreceptorCTLA-4CompetitivelybindtoB7Generateinhibitorysignal整理ppt37MechanismsofactionoftheinForthediscoveryanddevelopmentofamonoclonalantibodytherapythatunleashestheimmunesystemtocombatcancer.科學(xué)很有意思，但同時也很艱辛。我認為現(xiàn)在讓年輕科學(xué)家們?nèi)パ芯哭D(zhuǎn)化科學(xué)，做一些很快能應(yīng)用到臨床上的研究，會給他們施加過多壓力。他們應(yīng)該做的事情，是在基礎(chǔ)生物學(xué)領(lǐng)域提出一些重要問題，并時不時地思考一下它們是怎樣影響人體健康的，而不要把所有時間都花費在試圖“解決健康問題”上。我認為，真正好的基礎(chǔ)研究始終能占據(jù)一席之地。整理ppt38ForthediscoveryanddevelopmPD-1(Programmeddeath-1)

ExpressedonactivatedTcellsaswellasBcellsandNKcells

ItsligandsPD-L1andPD-L2expressedbyinflammatorytissuesandcancercells.

Inhibitechronicallyactivatedcellsandresponsesinperipheral,non-lymphoidtissues整理ppt39PD-1(Programmeddeath-1)ExpTheB7-CD28familiesofco-stimulatorsandco-inhibitoryreceptors整理ppt40TheB7-CD28familiesofco-stiCD40LMemberofTNFsuperfamilyExpressedonactivatedTcellsBindstoCD40expressedonAPCsIndireclyamplifyTcellresponsesbyenhancingtheexpressionof

B7moleculesinAPCs整理ppt41CD40LMemberofTNFsuperfamiRoleofCD40inTcellactivation.整理ppt42RoleofCD40inTcellactivatLiepingChenandDallasB.Flies,2013NatureImmunologyReview整理ppt43LiepingChenandDallasB.FliCo?stimulatoryandco?inhibitorysignallingpathwaysdownstreamofCD28familyreceptors.LiepingChenandDallasB.Flies,2013NatureImmunologyReview整理ppt44Co?stimulatoryandco?inhibitoTheseverallevelsofregulationinTcellco-signaling

Spatiotemporalregulationofco-signaling

Differentialinteractionsthroughmultipleinterfaces.整理ppt45Theseverallevelsofregulati重大疾病免疫治療的時代已經(jīng)來臨Science：重大疾病免疫療法是2013年最值得關(guān)注的六大科學(xué)領(lǐng)域之一免疫細胞治療展現(xiàn)驚人療效，權(quán)威期刊的紛紛評述免疫治療的成就整理ppt46重大疾病免疫治療的時代已經(jīng)來臨Science：重大疾病免疫療StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycle癌細胞抗原的釋放癌抗原的提呈腫瘤抗原特異性T細胞的

致敏與活化T細胞遷移到腫瘤T細胞的腫瘤局部浸潤T細胞識別癌細胞殺傷癌細胞整理ppt47StimulatoryandInhibitoryFac第二代抗體之一：抗腫瘤單克隆抗體(CTLA-4mAb)整理ppt48第二代抗體之一：抗腫瘤單克隆抗體(CTLA-4mAb)整理整理ppt49整理ppt49第二代抗體之二：抗腫瘤單克隆抗體(PD-1/PD-L1mAb)Anti-PD-1mAbAnti-PD-L1mAb整理ppt50第二代抗體之二：抗腫瘤單克隆抗體(PD-1/PD-L1mATheactivationofCD8+Tcells

Requirebothantigenrecognitionandsecondsignals

MayrequiresecondsignalprovidedbyCD4Thcells

intheconditionsthattendtoelicitweakinnateimmunereactions

latentviralinfectionorgantransplantstumor

整理ppt51TheactivationofCD8+TcellsRoleofco-stimulationandhelperTcellsintheCD8+Tcelldifferentiation整理ppt52Roleofco-stimulationandhelHierarchicalTcellexhaustionduringchronicinfection整理ppt53HierarchicalTcellexhaustionSubsetsofexhaustedTcellsandcombinatorialstrategiestoreverseexhaustion整理ppt54SubsetsofexhaustedTcellsaAcutoO,VDBartolo,andFMichel.TailoringT-cellreceptorsignalsbyproximalnegativefeedbackmechanisms.NatureReviewsImmunology8:699-712,2008.ChenL.Co-inhibitorymoleculesoftheB7-CD28familyinthecontrolofT-cellimmunity.NatureReviewsImmunology4:336-347,2004.GreenwaldRJ,GJFreeman,andAHSharpe.TheB7familyrevisited.AnnualReviewofImmunology23:515-548,2005.HuseM,EJQuann,andMMDavis.Shouts,whispersandthekissofdeath:directionalsecretioninTcells.NatureImmunology9:1105-1111,2008.SederRA,andRAhmed.SimilaritiesanddifferencesinCD4+andCD8+effectorandmemoryTcellgeneration.NatureImmunology4:835-842,2003

ChenLandFliesDB.MolecularmechanismsofTcellco-stimulationandco-inhibition.NatureReviewsImmunology12:227-242,2013Wherry,E.J.Tcellexhaustion.NatureImmunol.12,492–499(2011).WilliamsMA,andMJBevan.EffectorandmemoryCTLdifferentiation.AnnualReviewofImmunology25:171-192,2007.Selectedreadings整理ppt55AcutoO,VDBartolo,andFMiT細胞活化機制整理ppt56T細胞活化機制整理ppt1Na?veTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.整理ppt57Na?veTcellsBasedonthehis應(yīng)答誘導(dǎo)外周淋巴器官內(nèi)抗原識別T細胞擴增和分化分化的細胞進入循環(huán)效應(yīng)T細胞和其他白細胞遷移到感染部位在外周效應(yīng)T細胞遭遇抗原效應(yīng)T細胞活化T細胞的效應(yīng)功能整理ppt58應(yīng)答誘導(dǎo)外周淋巴器官內(nèi)T細胞擴增和分化分化的細胞效應(yīng)T細胞和.ActivationofTcellschangestheexpressionofseveralcell-surfacemolecules整理ppt59.ActivationofTcellschangesFunctionalresponsesofTcellsSecretionofcytokinesProliferationDifferentiationintoeffectorTcellsDifferentiationintomemoryTcells整理ppt60FunctionalresponsesofTcellSecretionofcytokinesOneoftheearliestdetectableresponsesofTcellstoantigenrecognitionPrinciplecytokine:IL-2DistinctsetsofcytokinessecretedbyeffectorTcells整理ppt61SecretionofcytokinesOneofClonalexpansionofTcells整理ppt62ClonalexpansionofTcells整理pAntigen-presentingcellsarerequiredforTcellactivation整理ppt63Antigen-presentingcellsarerSpecificantigenrecognitionbytheTcells;StableadhesionoftheTcellstotheAPCs;TransductionofactivatingsignalstotheTcells.TheinitiationofTcellresponsestospecificantigenrequiresEachoftheseeventsismediatedbydistinctsetsofmoleculesontheTcells.

整理ppt64SpecificantigenrecognitionTcellreceptorsandaccessorymolecules整理ppt65TcellreceptorsandaccessoryTcellreceptor(TCR)ThedefinitiveTcelllineagemarker

RecognitionofMHC-associatedpeptideantigen

DualspecificityMHCrestrictionAntigenspecificityNosignal-transducingfunctions整理ppt66Tcellreceptor(TCR)ThedefinTCRcomplexComposedofTCRandCD3

protein

整理ppt67TCRcomplexComposedofTCRandinvariantprotein,identicalinallTcellsregardlessofspecificityresponsibleforsignaling,butnotantigenrecognitionImmunoreceptortyrosine-basedactivationmotif

（ITAM)CD3Containstwocopiesofaconservedsequence:

tyrosine-X-X-leucine/isoleucineImportantforsignaltransductioninTcells整理ppt68invariantprotein,identicalAntigenrecognitionandsignalingfunctionsofTcellsAntigenrecognitionSignalingfunctions整理ppt69AntigenrecognitionandsignalCo-receptorsCD4andCD8MatureTcellsexpresseitherCD4orCD8,butnotbothInvolvedinMHC-restrictedTcellactivationCD4ClassⅡMHCmoleculesCD8ClassⅠMHCmoleculesAcategoryofmembraneproteinsthatenhanceTCRsignalingthroughsimultaneousbindingoftheMHCmolecules整理ppt70Co-receptorsCD4andCD8Acateg整理ppt71整理ppt16Two-signalHypothesis整理ppt72Two-signalHypothesis整理ppt17Signal1TCR-MHC+Aginteractionnotenoughforfullactivation整理ppt73Signal1TCR-MHC+AginteractiOverviewofTCRsignallingNatureReviewImmunol2013threemajorsignallingpathways整理ppt74OverviewofTCRsignallingNatuProvidedbyCostimulatoryMoleculesonactivatedAPCsAPCTCellB7CD28Signal2B7.1(CD80)B7.2(CD86)promotethesurvivalandexpansionoftheTcells整理ppt75ProvidedbyCostimulatoryMolAcomparisonbetweensignallingpathwaysinfullystimulatedandinanergizedTcellsdefectsatvariouspointsintheMAPK(mitogen-activatedproteinkinase)pathwaydownstreamofco-stimulationFathmanandLineberry,2007,NatureImmunology整理ppt76AcomparisonbetweensignallinFunctionsofco-stimulatorsinTcellactivationCyclosporinAFK506Rapamycin整理ppt77Functionsofco-stimulatorsinHigh-affinityIL-2receptorsarethree-chainstructuresthatarepresentonlyonactivatedTcells整理ppt78High-affinityIL-2receptorsaMediatedprimarilybyanautocrinegrowthpathwayProliferation整理ppt79MediatedprimarilybyanautocClonalexpansionThefrequencyofna?veTcellsspecificforagivenantigenis~1:105-6Ag-specificCD8+Tcells1:10

Ag-specificCD4+Tcells1:100/1000Ag-specificmemoryTcells1:104Agiseliminated整理ppt80ClonalexpansionThefrequencyPhasesofTcellresponsespriming整理ppt81PhasesofTcellresponsesprim整理ppt82整理ppt27Variationinsignal3causesnaiveCD4Tcellstoacquireseveraldistincttypesofeffectorfunctions整理ppt83Variationinsignal3causesnAmodelfortheregulationofearlyTH2differentiationbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology整理ppt84AmodelfortheregulationofAmodelforearlydeterminationofiTregfateversusTH17fatecontrolledbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology整理ppt85AmodelforearlydeterminatioAmodelforearlydeterminationofTeffcellfateversusTfhcellfatecontrolledbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology整理ppt86AmodelforearlydeterminatioCo-signalingreceptors

CD28ICOSCTLA-4PD-1CD40LOX40LMembraneproteinsexpressedonTcellsparticipateinresponsestoantigenbyrecognizingco-stimulators

orco-inhibitors

onAPCs,butnotrecognizingantigenTheIgsuperfamilyTNFreceptorsuperfamily整理ppt87Co-signalingreceptorsCD28MCD28ThediscoveryofCD28asaprototypeco-stimulatoryTCRprovidedevidenceforthetwo-signalmodelofTcellactivation,Firstidentifiedco-stimulatoryreceptortorecognizeB7moleculesonAPCsPrincipalreceptorfordeliveringsecondsignalsforTcellactivation整理ppt88CD28ThediscoveryofCD28asB7moleculesBest-definedco-stimulatorsIncludeB7.1(CD80)andB7.2(CD86)ExpressedmainlyonAPCs

IncreasedbymicrobialproductsandcytokinesImportantfortheactivationofna?veTcellsbyinteracting

with

CD28onTcells整理ppt89B7moleculesBest-definedco-stICOS(Inducibleco-stimulator)

ExpressedonactivatedTcellsBindsICOSL(ICOSligandorB7-H2)

Importantfortheactivationofeffectorcellstosecretesome

cytokines,suchasIL-4andIFN-

particularlyimportantfroenablingCD4TcellstohelpercellsforB-cellresponsessuchasisotypeswitching整理ppt90ICOS(Inducibleco-stimulator)CTLA-4ExpressedonrecentlyactivatedTcellscompetewithCD28fortheligandsCD80andCD86(with20Xhigheraffinity)

Actsasasignaldampenerduringtheearlystagesofactivationofna?veandmemoryTcells(24-48hrafterantigenpresentation)

Playacentralroleinself-tolerance整理ppt91CTLA-4ExpressedonrecentlyMechanismsofactionoftheinhibitoryreceptorCTLA-4CompetitivelybindtoB7Generateinhibitorysignal整理ppt92MechanismsofactionoftheinForthediscoveryanddevelopmentofamonoclonalantibodytherapythatunleashestheimmunesystemtocombatcancer.科學(xué)很有意思，但同時也很艱辛。我認為現(xiàn)在讓年輕科學(xué)家們?nèi)パ芯哭D(zhuǎn)化科學(xué)，做一些很快能應(yīng)用到臨床上的研究，會給他們施加過多壓力。他們應(yīng)該做的事情，是在基礎(chǔ)生物學(xué)領(lǐng)域提出一些重要問題，并時不時地思考一下它們是怎樣影響人體健康的，而不要把所有時間都花費在試圖“解決健康問題”上。我認為，真正好的基礎(chǔ)研究始終能占據(jù)一席之地。整理ppt93ForthediscoveryanddevelopmPD-1(Programmeddeath-1)

ExpressedonactivatedTcellsaswellasBcellsandNKcells

ItsligandsPD-L1andPD-L2expressedbyinflammatorytissuesandcancercells.

Inhibitechronicallyactivatedcellsandresponsesinperipheral,non-lymphoidtissues整理ppt94PD-1(Programmeddeath-1)ExpTheB7-CD28familiesofco-stimulatorsandco-inhibitoryreceptors整理ppt95TheB7-CD28familiesofco-stiCD40LMemberofTNFsuperfamilyExpressedonactivatedTcellsBindstoCD40expressedonAPCsIndireclyamplifyTcellresponsesbyenhancingtheexpressionof

B7moleculesinAPCs整理ppt96CD40LMemberofTNFsuperfamiRoleofCD40inTcellactivation.整理ppt97RoleofCD40inTcellactivatLiepingChenandDallasB.Flies,2013NatureImmunologyReview整理ppt98LiepingChenandDallasB.FliCo?stimulatoryandco?inhibitorysignallingpathwaysdownstreamofCD28familyreceptors.LiepingChenandDallasB.Flies,2013NatureImmunologyReview整理ppt99Co?stimulatoryandco?inhibitoTheseverallevelsofregulationinTcellco-signaling

Spatiotemporalregulationofco-signaling

Differentialinteractionsthroughmultipleinterfaces.整理ppt100Theseverallevelsofregulati重大疾病免疫治療的時代已經(jīng)來臨Science：重大疾病免疫療法是2013年最值得關(guān)注的六大科學(xué)領(lǐng)域之一免疫細