T细胞亚群ppt课件.ppt

T细胞亚群 1 2 3 Classesoflymphocytes 4 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 5 Tcellsubsets Tcellsand TcellsCD4 TcellsandCD8 TNa veTcells 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 6 TCellsubsets 7 Tcells expressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies inthesmallbowelmucosaandintheskinofmouse Intheskin knownasadendriticepidermalTcell DETC donotrecognizeMHC associatedpeptideantigensandarenotMHCrestricted maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress suchasmicrobialheatshockproteins mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens 8 Jensen K D etal Thymicselectiondetermines Tcelleffectorfate antigen naivecellsmakeinterleukin 17andantigen experiencedcellsmakeinterferon Immunity29 90 100 2008 Epithelial TcellandPeripheral TcellCD27 IL 17 TcellsandCD27 IFN Tcells Subsetsof Tcells 9 Developmentalprogrammingof Tcellsubsets CuaDJ etal NaturereviewImmunology 2010 10 MartinBetal IL 17 Producing TcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals Immunity31 321 330 2009 Theyshowthat T 17cellsadditionallyexpressIL 23R andtheinnatereceptorsTLR2anddectin 1 whichrecognizearchetypicalandfungalconstituents These T 17cellsusethesereceptorstorapidlyproduceIL 17inresponsetobystandercell derivedIL 23andtobacteriaandfungiwithoutconcomitantTCRstimulation Oneoftherolesof T 17 derivedmaybeindirectordirectamplificationofIL 17productioninTh17cells Sutton C E etal Interleukin 1andIL 23induceinnateIL 17productionfrom Tcells amplifyingTh17responsesandautoimmunity Immunity31 331 341 2009 Thisreportshowsthat TcellshaveanearlyroleinpromotingCNSinflammation Theauthorssuggestthatinnatecell producedIL 17directlyenhancesdevelopmentofMOG specificTh17cells AmajorinnatesourceofIL 17 11 InnateActivationofIL 17 ProductionbyaSpecialized TCellSubset KapsenbergML Immunity 2009 12 Witherden etal ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelial Tcellactivation Science2010SepIdentifyanepithelial Tcells specificcostimulatorymolecule JAMLPetermannF etal TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL 23 dependengmechanism Immunity 2010SepIL 23 activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3 Tregcellsinvivo Twonewpapersabout TCellpublishedinthismonth 13 14 Na veTcellsMatureTcellsthathavenotpreviouslyencounteredantigen Preferentialmigrationtosecondarylymphoidorgans lymphnodes wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort livedMemoryTcellsLong lived functionallysilentcells MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous centralandeffector BasedonthehistoryofantigenencounterandthestageofTcellactivation 15 16 CentralmemoryTcellsexpressCCR7andL selectin andhometolymphnodes limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeEffectormemoryTcellsdonotexpressCCR7orL selectin andhometoperipheraltissues especiallymucosa produceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch Basedontheirhomingpropertiesandeffectorfunctions SubsetsofmemoryTcells 17 CD4 CD8 CD4 18 Th1 Th2hypothesis1986CoffmanandMossmanTh172006 DiscoveryofCD4 Thcellsubsets 19 ThesubsetsofCD4 Thcells Howtheyareinduced WhatcytokinestheyproduceWhateffectormechanismstheyactivate Th0 20 Cytokines StimulithatinfluencethepatternofThcelldifferentiation HighdosesofantigenwithoutadjuvantsDifferentsubsetsofdendriticcellsmayexistThegeneticmakeupofthehost 21 PropertiesofCD4 Th1andTh2subsets 22 DifferentiationofTh1Subset StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcellsListeria mycobacteriaandLeishmania ImportantcytokinesfortheTh1differentiation Importanttranscriptionfactors TF fortheTh1differentiation IL 12IFN IL 18typeIIFNs inhuman T bet masterregulatorSTAT4STAT1 23 ThemolecularbasisofTh1differentiation TheinterplayofsignalsfromtheTcellreceptor thecytokinesIFN andIL 12 andtheTFT bet STAT1 andSTAT4 IL 12STAT 4IFN STAT 1AgrecognitionbyTCRT betApositiveamplificationloopbetweenT betandIFN 24 DifferentiationofTh1subsets 25 DifferentiationofTh2Subset ImportantTFfortheTh2differentiation StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthandallergens ImportantcytokinesfortheTh2differentiation IL 4 GATA 3 masterregulatorSTAT6 26 ThemolecularbasisofTh2differentiation TheinterplayofsignalsfromtheTcellreceptor thecytokineIL 4 andtheTFGATA 3andSTAT6 27 GATA 3 EnhancesexpressionoftheTh2cytokinegenesIL 4 IL 5 andIL 13by1 directlyinteractingwiththepromotersofthesegenes2 causingchromatinremodelingEnhancesitsownexpressionviaapositivefeedbackloopBlocksTh1differentiation AmasterregulatorofTh2differentiation 28 DevelopmentofTh2subsets 29 DevelopmentofTh1andTh2subsets 30 31 DifferentiationofTh17Subset Stimulatedbyzymosan fungus myobacteria ImportantcytokinesfortheTh17differentiation Importanttranscriptionfactors TF fortheTh17differentiation IL 6TGF IL 23IL 21 ROR t masterregulatorROR STAT3AhR 32 Th17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation Veldhoenetal ThearylhydrocarbonreceptorlinksTH17 cell mediatedautoimmunitytoenvironmentaltoxins Nature453 106 109 2008 Quintanaetal ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor Nature453 65 71 2008 Kimuraetal ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells Proc Natl Acad Sci USA105 9721 9726 2008 Veldhoen etal NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells JExpMed 2009IMDMisbetterthan1640forTh17invitrodifferentiation 33 ThedifferentiationofTh17Subset 34 CD4 CD25 RegulatoryTcells Tregcells AsubsetofCD4 CD25 TcellsexpressingFoxp3Naturallypresentinimmunesystem constitute5 10 ofperipheralCD4 TcellsSuppressimmuneresponsesandmaintainself tolerance 35 Sakaguchietal Immunologicself tolerancemaintainedbyactivatedTcellsexpressingIL 2receptoralpha chains CD25 Breakdownofasinglemechanismofself tolerancecausesvariousautoimmunediseases JImmunol1995Horietal ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3 Science2003Fontenotetal Foxp3programsthedevelopmentandfunctionofCD4 CD25 regulatoryTcells NatureImmunol2003 LandmarkpapersaboutTreg 36 NaturalTregcells nTreg thymicderived highlycontrolledbythymicmicroenvironmentInducedTregcells iTreg peripherallygenerated SubsetsofTregcells 37 TCRCo stimulationCytokine mediatedsignals 38 Josefowiczetal Immunity 2009 DifferentiationofthymicandinducedTregcells 39 MechanismsofTregcells mediatedsuppression 40 DirectlysuppressresponderFoxp3 TcellsIndirectlyblocktheactivationofFoxp3 TcellsbysuppressingthefunctionofAPC MechanismsofTregcells mediatedsuppression 41 MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3 Tcells Shevach Immunity 2009 42 MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3 Tcells Shevach Immunity 2009 43 44 Subsets inthemaking FollicularhelperTcells TFH Th9Th22 45 FollicularhelperTcells TFH PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL 21 whichactsinanautocrinemannertogetherwithIL 6promotetheirdifferentiationandexpansionDependontheBcl 6transcriptionfactorEssentialforthegenerationofhigh affinityisotypeswitchedantibodiesandBcellmemory 46 Vogelzang etal GenerationofTfollicularhelpercellsismediatedbyinterleukin 21butindependentofThelper1 2 or17celllineages Immunity29 138 149 2008 Zaretsky etal TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens J Exp Med 206 991 999 2009 Kingetal IL 4 producingCD4 TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells J Exp Med 206 1001 1007 2009 Rainhardtetal Cytokine secretingfollicularTcellsshapetheantibodyrepertoire NatureImmunol 10 385 393 2009 ThreestudiesusedIL 4reportermiceandshowedthat duringhelminthinfection mostIL 4 expressingCD4 TcellsalsoexpressedtheTFHcellmarkersCXCR5 programmedcelldeathprotein1 PD 1 inducibleTcellco stimulator ICOS Bcelllymphoma6 BCL 6 andIL 21andlocalizedtotheBcellfolliclesJohnstonetal Bcl6andBlimp 1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldifferentiation Science325 1006 1010 2009 47 Th9 Veldhoen M etal Transforminggrowthfactor reprograms thedifferentiationofThelper2cellsandpromotesaninterleukin9 producingsubset Nat Immunol 9 1341 1346 2008 Th2cellscanchangeintoanI