复旦大学课件T细胞亚群10-17.ppt

,T细胞亚群,何睿ruihe免疫学系上海医学院复旦大学,Classesoflymphocytes,T细胞亚群T细胞活化分子机制T细胞免疫应答及其效应,自身免疫和超敏反应,Tcellsubsets,TcellsandTcellsCD4+TcellsandCD8+TNaveTcells（初始T细胞）EffectorTcells（效应T细胞）MemoryTcells（记忆T细胞）Thelper(Th)辅助性CD4+T细胞CytotoxicTcells(CTLs)细胞毒性CD8+T细胞RegulatoryTcells(Tregs)调节性CD4+T细胞,TCellsubsets,Tcells,expressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.,Jensen,K.D.etal.ThymicselectiondeterminesTcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferonImmunity29,90100(2008).,EpithelialTcellandPeripheralTcellCD27-IL-17+TcellsandCD27+IFN-+Tcells,SubsetsofTcells,DevelopmentalprogrammingofTcellsubsets.,CuaDJ,etal.NaturereviewImmunology,2010,MartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321330(2009).TheyshowthatT-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfungalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-17productioninTh17cells.Sutton,C.E.etal.Interleukin-1andIL-23induceinnateIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.Immunity31,331341(2009).ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.,AmajorinnatesourceofIL-17,InnateActivationofIL-17-ProductionbyaSpecializedTCellSubset,KapsenbergML.Immunity,2009,Witherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelialTcellactivation.Science2010SepIdentifyanepithelialTcells-specificcostimulatorymolecule,JAMLPetermannF,etal.TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcellsinvivo.,TwonewpapersaboutTCellpublishedinthismonth,NaveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector),BasedonthehistoryofantigenencounterandthestageofTcellactivation.,CentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,duceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.,Basedontheirhomingpropertiesandeffectorfunctions.,SubsetsofmemoryTcells,CD4+,CD8+,CD4+,Th1-Th2hypothesis1986CoffmanandMossmanTh172006,DiscoveryofCD4+Thcellsubsets,ThesubsetsofCD4+Thcells,Howtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivate,Th0,Cytokines,StimulithatinfluencethepatternofThcelldifferentiation,HighdosesofantigenwithoutadjuvantsDifferentsubsetsofdendriticcellsmayexistThegeneticmakeupofthehost,PropertiesofCD4+Th1andTh2subsets,DifferentiationofTh1Subset,StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcellsListeria,mycobacteriaandLeishmania,ImportantcytokinesfortheTh1differentiation,Importanttranscriptionfactors(TF)fortheTh1differentiation,IL-12IFN-IL-18typeIIFNs(inhuman),T-bet:masterregulatorSTAT4STAT1,ThemolecularbasisofTh1differentiation,TheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4,IL-12STAT-4IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-,DifferentiationofTh1subsets,DifferentiationofTh2Subset,ImportantTFfortheTh2differentiation,StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthandallergens,ImportantcytokinesfortheTh2differentiation,IL-4,GATA-3:masterregulatorSTAT6,ThemolecularbasisofTh2differentiation,TheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6,GATA-3,EnhancesexpressionoftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodelingEnhancesitsownexpressionviaapositivefeedbackloopBlocksTh1differentiation,AmasterregulatorofTh2differentiation,DevelopmentofTh2subsets,DevelopmentofTh1andTh2subsets,DifferentiationofTh17Subset,Stimulatedbyzymosan,fungus,myobacteria,ImportantcytokinesfortheTh17differentiation,Importanttranscriptionfactors(TF)fortheTh17differentiation,IL-6TGF-IL-23IL-21,ROR-t:masterregulatorROR-STAT3AhR,Th17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.Veldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.Nature453,106109(2008).Quintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.Nature453,6571(2008).Kimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl.Acad.Sci.USA105,97219726(2008).Veldhoen,etal.NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009IMDMisbetterthan1640forTh17invitrodifferentiation,ThedifferentiationofTh17Subset,CD4+CD25+RegulatoryTcells(Tregcells),AsubsetofCD4+CD25+TcellsexpressingFoxp3Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-tolerance,Sakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995Horietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003Fontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003,LandmarkpapersaboutTreg,NaturalTregcells(nTreg)thymicderived,highlycontrolledbythymicmicroenvironmentInducedTregcells(iTreg)peripherallygenerated,SubsetsofTregcells,TCRCo-stimulationCytokine-mediatedsignals,Josefowiczetal.Immunity,2009,DifferentiationofthymicandinducedTregcells,MechanismsofTregcells-mediatedsuppression,DirectlysuppressresponderFoxp3-TcellsIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPC,MechanismsofTregcells-mediatedsuppression,MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-Tcells,Shevach.Immunity,2009,MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-Tcells,Shevach.Immunity,2009,Subsets“inthemaking”,FollicularhelperTcells(TFH)Th9Th22,FollicularhelperTcells(TFH),PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory,Vogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immunity29,138149(2008).Zaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.206,991999(2009).Kingetal.IL-4-producingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.J.Exp.Med.206,10011007(2009).Rainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.NatureImmunol.10,385393(2009).ThreestudiesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedtotheBcellfolliclesJohnstonetal.Bcl6andBlimp-1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldifferentiation.Science325,10061010(2009).,Th9,Veldhoen,M.etal.Transforminggrowthfactor-reprogramsthedifferentiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,13411346(2008).Th2cellscanchangeinto