T 细胞亚群细胞亚群 免疫学系免疫学系复旦大学复旦大学123Classesoflymphocytes4vT细胞亚群细胞亚群vT细胞活化分子机制细胞活化分子机制vT细胞免疫应答及其效应细胞免疫应答及其效应v自身免疫和超敏反应自身免疫和超敏反应5vTcellsubsetsqTcellsandTcellsqCD4+TcellsandCD8+TqNaveTcells（初始（初始T细胞）细胞）EffectorTcells（效应（效应T细胞）细胞）MemoryTcells（记忆（记忆T细胞）细胞）qThelper(Th)辅助性辅助性CD4+T细胞细胞CytotoxicTcells(CTLs)细胞毒性细胞毒性CD8+T细胞细胞RegulatoryTcells(Tregs)调节性调节性CD4+T细胞细胞6TCellsubsetsClassFunctionsAntigenreceptorandspecificitySelectedmarkersPercentoftotallymphocytes(human)TlymphocytesBloodLymphnodeSpleenCD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)Macrophageactivation(cell-mediatedimmunity)heterodimersDiversespecificitiesforpeptide-classIIMHCcomplexesCD3+,CD4+,CD8-50-60*50-6050-60CD8+cytotoxicTlymphocytesKillingofcellinfectedwithmicrobes,killingoftumorcellsheterodimersDiversespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunctionofotherTcells(regulationofimmuneresponses,maintenanceofself-tolerance)heterodimersCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesaswell)Rare1010TlymphocytesHelperandcytotoxicfunctions(innateimmunity)heterodimersLimitedspecificitiesforpeptideandnonpeptideantigensCD3+,CD4,andCD8variable7TcellsexpressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.8Jensen,K.D.et al.ThymicselectiondeterminesTcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferon Immunity29,90100(2008).pEpithelialTcellandPeripheralTcellpCD27-IL-17+TcellsandCD27+IFN- +TcellsSubsetsofTcells9DevelopmentalprogrammingofTcellsubsets.CuaDJ,etal.NaturereviewImmunology,201010uMartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321330(2009).TheyshowthatT-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfungalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-17productioninTh17cells.uSutton,C.E.et al.Interleukin-1andIL-23induceinnateIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.Immunity31,331341(2009).ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-1711InnateActivationofIL-17-ProductionbyaSpecializedTCellSubsetKapsenbergML.Immunity,200912uWitherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelialTcellactivation.Science2010SepIdentifyanepithelialTcells-specificcostimulatorymolecule,JAMLuPetermannF,etal.TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcellsinvivo.TwonewpapersaboutTCellpublishedinthismonth1314qNaveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenqEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedqMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.15NaiveTcellsEffectorTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferentiallytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-SurfaceproteinexpressionHigh-affinityIL-2receptorLowHighLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)HighLowLoworvariableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmall16uCentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeuEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,especiallymucosa.produceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.Basedontheirhomingpropertiesandeffectorfunctions.SubsetsofmemoryTcells17CD4+CD8+CD4+18Th1-Th2hypothesis1986CoffmanandMossmanTh172006DiscoveryofCD4+Thcellsubsets19ThesubsetsofCD4+ThcellsHowtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivateTh020qCytokinesStimulithatinfluencethepatternofThcelldifferentiationqHighdosesofantigenwithoutadjuvantsqDifferentsubsetsofdendriticcellsmayexistqThegeneticmakeupofthehost21PropertiesofCD4+Th1andTh2subsets22DifferentiationofTh1SubsetvStimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcells Listeria,mycobacteriaandLeishmaniavImportantcytokinesfortheTh1differentiationvImportanttranscriptionfactors(TF)fortheTh1differentiationIL-12IFN- IL-18typeIIFNs(inhuman)T-bet:masterregulatorSTAT4STAT123ThemolecularbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN- andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4IFN- STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN- 24DifferentiationofTh1subsets25DifferentiationofTh2SubsetvImportantTFfortheTh2differentiationvStimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthandallergensvImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregulatorSTAT626ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-327GATA-3qEnhancesexpressionoftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodelingqEnhancesitsownexpressionviaapositivefeedbackloopqBlocksTh1differentiationAmasterregulatorofTh2differentiation28DevelopmentofTh2subsets29DevelopmentofTh1andTh2subsets3031DifferentiationofTh17SubsetvStimulatedbyzymosan,fungus,myobacteriavImportantcytokinesfortheTh17differentiationvImportanttranscriptionfactors(TF)fortheTh17differentiationIL-6TGF- IL-23IL-21ROR- t:masterregulatorROR- STAT3AhR32Th17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.uVeldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.Nature453,106109(2008).uQuintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.Nature453,6571(2008).uKimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc. 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USA105,97219726(2008).uVeldhoen,etal.NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009IMDMisbetterthan1640forTh17invitrodifferentiation33ThedifferentiationofTh17Subset34CD4+CD25+RegulatoryTcells(Tregcells)AsubsetofCD4+CD25+TcellsexpressingFoxp3Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-tolerance35uSakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995uHorietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003uFontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTreg36pNaturalTregcells(nTreg)thymicderived,highlycontrolledbythymicmicroenvironmentpInducedTregcells(iTreg)peripherallygeneratedSubsetsofTregcells37lTCRlCo-stimulationlCytokine-mediatedsignals38Josefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcells39MechanismsofTregcells-mediatedsuppression40pDirectlysuppressresponderFoxp3-TcellspIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppression41MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,200942MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,20094344Subsets“inthemaking”pFollicularhelperTcells(TFH)pTh9pTh2245FollicularhelperTcells(TFH)PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory46uVogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immunity29,138149(2008).uZaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J. 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Med.206,16531660(2009).uElyaman,W.et al.IL-9inducesdifferentiationofTH17cellsandenhancesfunctionofFoxP3+naturalregulatoryTcells.Proc. Natl. Acad. Sci. USA106,1288512890(2009).uBeriouetal.TGF-betainducesIL-9fromhumanTh17cells.JImmunol.20104849uDuhen,etal.Productionofinterleukin22butnotinterleukin17byasubsetofhumanskin-homingmemoryTcells.Nature Immunol.10,857863(2009).uTrifari,etal.IdentificationofahumanhelperTcellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17,TH1andTH2cells.Nature Immunol.10,864871(2009).Th22Inhuman,butnotmouseExpressIL-22butnotIL-17orROR-t:Maypresentaskin-homingsubsetresponsibleforskininflammationsuchaspsoriasis5051Apossiblehierarchyofstability52pTheflexibilityofTcellsubsets?pWhataretheenvironmental(extrinsic)factorsthatallowforplasticity?pWhatregulateslineagecommitmentversusflexibility?pWhydoweneedsomanyfunctionalsubsets?Questions53