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1、第1页/共53页第2页/共53页Classesoflymphocytes第3页/共53页vT细胞亚群vT细胞活化分子机制vT细胞免疫应答及其效应v自身免疫和超敏反应第4页/共53页vTcellsubsetsqTcellsandTcellsqCD4+TcellsandCD8+TqNaveTcells（初始T细胞）EffectorTcells（效应T细胞）MemoryTcells（记忆T细胞）qThelper(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细胞第5页/共53页TCellsubs
2、etsClassFunctionsAntigenreceptorandspecificitySelectedmarkersPercentoftotallymphocytes(human)TlymphocytesBloodLymphnodeSpleenCD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)Macrophageactivation(cell-mediatedimmunity)heterodimersDiversespecificitiesforpeptide-classIIMHCcomplexesCD3+,CD4+,C
3、D8-50-60*50-6050-60CD8+cytotoxicTlymphocytesKillingofcellinfectedwithmicrobes,killingoftumorcellsheterodimersDiversespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunctionofotherTcells(regulationofimmuneresponses,maintenanceofself-tolerance)heterodimer
4、sCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesaswell)Rare1010TlymphocytesHelperandcytotoxicfunctions(innateimmunity)heterodimersLimitedspecificitiesforpeptideandnonpeptideantigensCD3+,CD4,andCD8variable第6页/共53页TcellsexpressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbow
5、elmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptivei
6、mmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.第7页/共53页Jensen,K.D.et al.ThymicselectiondeterminesTcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferon Immunity29,90100(2008).pEpithelialTcellandPeripheralTcellpCD27-IL
7、-17+TcellsandCD27+IFN-+TcellsSubsetsofTcells第8页/共53页DevelopmentalprogrammingofTcellsubsets.CuaDJ,etal.NaturereviewImmunology,2010第9页/共53页uMartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321330(2009).TheyshowthatT-17cellsadditionallyexp
8、ressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfungalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificatio
9、nofIL-17productioninTh17cells.uSutton,C.E.et al.Interleukin-1andIL-23induceinnateIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.Immunity31,331341(2009).ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesde
10、velopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-17第10页/共53页InnateActivationofIL-17-ProductionbyaSpecializedTCellSubsetKapsenbergML.Immunity,2009第11页/共53页uWitherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelialTcellactivation.Science2010SepIdentifyanepithelialTce
11、lls-specificcostimulatorymolecule,JAMLuPetermannF,etal.TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFox
12、p3+Tregcellsinvivo.TwonewpapersaboutTCellpublishedinthismonth第12页/共53页第13页/共53页qNaveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenqEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeli
13、minateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedqMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.第14页/共53页Naiv
14、eTcellsEffectorTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferentiallytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-Su
15、rfaceproteinexpressionHigh-affinityIL-2receptorLowHighLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)HighLowLoworvariableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;m
16、orecytoplasmSmall第15页/共53页uCentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeuEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,especiallymucosa.produ
17、ceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.Basedontheirhomingpropertiesandeffectorfunctions.SubsetsofmemoryTcells第16页/共53页CD4+CD8+CD4+第17页/共53页Th1-Th2hypothesis1986CoffmanandMossmanTh172006DiscoveryofCD4+Thcellsubsets第18页/共53页ThesubsetsofCD4+ThcellsHowtheyareinduced,Whatcytokine
18、stheyproduceWhateffectormechanismstheyactivateTh0第19页/共53页qCytokinesStimulithatinfluencethepatternofThcelldifferentiationqHighdosesofantigenwithoutadjuvantsqDifferentsubsetsofdendriticcellsmayexistqThegeneticmakeupofthehost第20页/共53页PropertiesofCD4+Th1andTh2subsets第21页/共53页DifferentiationofTh1Subsetv
19、StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcells Listeria,mycobacteriaandLeishmaniavImportantcytokinesfortheTh1differentiationvImportanttranscriptionfactors(TF)fortheTh1differentiationIL-12IFN-IL-18typeIIFNs(inhuman)T-bet:masterregulatorSTAT4STAT1第22页/共53页Themolecularbasisof
20、Th1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-第23页/共53页DifferentiationofTh1subsets第24页/共53页DifferentiationofTh2SubsetvImportantTFfortheTh2differ
21、entiationvStimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthandallergensvImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregulatorSTAT6第25页/共53页ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTc
22、ellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-3第26页/共53页GATA-3qEnhancesexpressionoftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodelingqEnhancesitsownexpressionviaa
23、positivefeedbackloopqBlocksTh1differentiationAmasterregulatorofTh2differentiation第27页/共53页DevelopmentofTh2subsets第28页/共53页DevelopmentofTh1andTh2subsets第29页/共53页第30页/共53页DifferentiationofTh17SubsetvStimulatedbyzymosan,fungus,myobacteriavImportantcytokinesfortheTh17differentiationvImportanttranscripti
24、onfactors(TF)fortheTh17differentiationIL-6TGF-IL-23IL-21ROR-t:masterregulatorROR-STAT3AhR第31页/共53页Th17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.uVeldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.N
25、ature453,106109(2008).uQuintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.Nature453,6571(2008).uKimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl.Acad.Sci.USA105,97219726(2008).uVeldhoen,etal.Naturalagonistsfo
26、rarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009IMDMisbetterthan1640forTh17invitrodifferentiation第32页/共53页ThedifferentiationofTh17Subset第33页/共53页CD4+CD25+RegulatoryTcells(Tregcells)AsubsetofCD4+CD25+TcellsexpressingFoxp3Naturallypresentinimmunesys
27、tem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-tolerance第34页/共53页uSakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995uHoriet
28、al.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003uFontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTreg第35页/共53页pNaturalTregcells(nTreg)thymicderived,highlycontrolledbythymicmicroenvironmentpInducedTregce
29、lls(iTreg)peripherallygeneratedSubsetsofTregcells第36页/共53页lTCRlCo-stimulationlCytokine-mediatedsignals第37页/共53页Josefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcells第38页/共53页MechanismsofTregcells-mediatedsuppression第39页/共53页pDirectlysuppressresponderFoxp3-TcellspIndirectlyblocktheact
30、ivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppression第40页/共53页MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,2009第41页/共53页MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-
31、TcellsShevach.Immunity,2009第42页/共53页第43页/共53页Subsets“inthemaking”pFollicularhelperTcells(TFH)pTh9pTh22第44页/共53页FollicularhelperTcells(TFH)PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDe
32、pendontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory第45页/共53页uVogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immunity29,138149(2008).uZaretsky,etal.Tfollicularhelpercel
33、lsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.206,991999(2009).uKingetal.IL-4-producingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.J.Exp.Med.206,10011007(2009).uRainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.Nature Im
34、munol.10,385393(2009).ThreestudiesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedtotheBcellfolliclesuJohnstonetal.B
35、cl6andBlimp-1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldifferentiation.Science325,10061010(2009).第46页/共53页Th9uVeldhoen,M.et al.Transforminggrowthfactor-reprogramsthedifferentiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,13411346(2008).Th2cellscanchan
36、geintoanIL-9-producingTcelltypeuNowak,E.C.et al.IL-9asamediatorofTh17-driveninflammatorydisease.J.Exp.Med.206,16531660(2009).uElyaman,W.et al.IL-9inducesdifferentiationofTH17cellsandenhancesfunctionofFoxP3+naturalregulatoryTcells.Proc.Natl.Acad.Sci.USA106,1288512890(2009).uBeriouetal.TGF-betainduces
37、IL-9fromhumanTh17cells.JImmunol.2010第47页/共53页第48页/共53页uDuhen,etal.Productionofinterleukin22butnotinterleukin17byasubsetofhumanskin-homingmemoryTcells.Nature Immunol.10,857863(2009).uTrifari,etal.IdentificationofahumanhelperTcellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17
38、,TH1andTH2cells.Nature Immunol.10,864871(2009).Th22Inhuman,butnotmouseExpressIL-22butnotIL-17orROR-t:Maypresentaskin-homingsubsetresponsibleforskininflammationsuchaspsoriasis第49页/共53页第50页/共53页Apossiblehierarchyofstability第51页/共53页pTheflexibilityofTcellsubsets?pWhataretheenvironmental(extrinsic)factorsthatallowforplasticity?pWhatregulateslineagecommitmentversusflexibility?pWhydoweneedsomanyfunctionalsubsets?Questions第52页/共53页感谢您的观看！第53页/共53页