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1、ClassesoflymphocytesvT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vTcellsubsetsqTcellsandTcellsqCD4+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
2、)调节性调节性CD4+T细胞细胞TCellsubsetsClassFunctionsAntigenreceptorandspecificitySelectedmarkersPercentoftotallymphocytes(human)TlymphocytesBloodLymphnodeSpleenCD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)Macrophageactivation(cell-mediatedimmunity)heterodimersDiversespecificitiesforpeptide-class
3、IIMHCcomplexesCD3+,CD4+,CD8-50-60*50-6050-60CD8+cytotoxicTlymphocytesKillingofcellinfectedwithmicrobes,killingoftumorcellsheterodimersDiversespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunctionofotherTcells(regulationofimmuneresponses,maintenanceofs
4、elf-tolerance)heterodimersCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesaswell)Rare1010TlymphocytesHelperandcytotoxicfunctions(innateimmunity)heterodimersLimitedspecificitiesforpeptideandnonpeptideantigensCD3+,CD4,andCD8variableTcellsexpressalimitednumberofTCRsabundantinepithelialtissuesofcertainspec
5、ies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeni
6、nnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.Jensen,K.D.et al.ThymicselectiondeterminesTcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferon Immunity29,90100(2008).pEpithelialTcellandPeripheralTcel
7、lpCD27-IL-17+TcellsandCD27+IFN-+TcellsSubsetsofTcellsDevelopmentalprogrammingofTcellsubsets.CuaDJ,etal.NaturereviewImmunology,2010uMartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321330(2009).TheyshowthatT-17cellsadditionallyexpressIL-
8、23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfungalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-1
9、7productioninTh17cells.uSutton,C.E.et al.Interleukin-1andIL-23induceinnateIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.Immunity31,331341(2009).ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopme
10、ntofMOG-specificTh17cells.AmajorinnatesourceofIL-17InnateActivationofIL-17-ProductionbyaSpecializedTCellSubsetKapsenbergML.Immunity,2009uWitherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelialTcellactivation.Science2010SepIdentifyanepithelialTcells-specificcostimulatory
11、molecule,JAMLuPetermannF,etal.TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcellsinvivo.Twonew
12、papersaboutTCellpublishedinthismonthqNaveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenqEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationt
13、ositesofinfectionorinflammationShort-livedqMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.NaiveTcellsEffectorTcellsMemoryTcellsMigrationPreferenti
14、allytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferentiallytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-SurfaceproteinexpressionHigh-affinityIL-2receptorLowHi
15、ghLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)HighLowLoworvariableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmalluCentralmemoryTcellsexpressCCR7andL
16、-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeuEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,especiallymucosa.produceeffectorcytokinesuponantigenicstimulationdonotproliferatemu
17、ch.Basedontheirhomingpropertiesandeffectorfunctions.SubsetsofmemoryTcellsCD4+CD8+CD4+Th1-Th2hypothesis1986CoffmanandMossmanTh172006DiscoveryofCD4+ThcellsubsetsThesubsetsofCD4+ThcellsHowtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivateTh0qCytokinesStimulithatinfluencethepatter
18、nofThcelldifferentiationqHighdosesofantigenwithoutadjuvantsqDifferentsubsetsofdendriticcellsmayexistqThegeneticmakeupofthehostPropertiesofCD4+Th1andTh2subsetsDifferentiationofTh1SubsetvStimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcells Listeria,mycobacteriaandLeishmaniavImport
19、antcytokinesfortheTh1differentiationvImportanttranscriptionfactors(TF)fortheTh1differentiationIL-12IFN-IL-18typeIIFNs(inhuman)T-bet:masterregulatorSTAT4STAT1ThemolecularbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4
20、IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-DifferentiationofTh1subsetsDifferentiationofTh2SubsetvImportantTFfortheTh2differentiationvStimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthanda
21、llergensvImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregulatorSTAT6ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-3GATA-3qEnhancesexpressionoftheTh
22、2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodelingqEnhancesitsownexpressionviaapositivefeedbackloopqBlocksTh1differentiationAmasterregulatorofTh2differentiationDevelopmentofTh2subsetsDevelopmentofTh1andTh2subsetsDifferentiationofTh17Subset
23、vStimulatedbyzymosan,fungus,myobacteriavImportantcytokinesfortheTh17differentiationvImportanttranscriptionfactors(TF)fortheTh17differentiationIL-6TGF-IL-23IL-21ROR-t:masterregulatorROR-STAT3AhRTh17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.uVe
24、ldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.Nature453,106109(2008).uQuintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.Nature453,6571(2008).uKimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthed
25、evelopmentofTh17cells.Proc.Natl.Acad.Sci.USA105,97219726(2008).uVeldhoen,etal.NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009IMDMisbetterthan1640forTh17invitrodifferentiationThedifferentiationofTh17SubsetCD4+CD25+RegulatoryTcells
26、(Tregcells)AsubsetofCD4+CD25+TcellsexpressingFoxp3Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-toleranceuSakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanis
27、mofself-tolerancecausesvariousautoimmunediseases.JImmunol1995uHorietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003uFontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTregpNaturalTregcells(nTreg)thymicder
28、ived,highlycontrolledbythymicmicroenvironmentpInducedTregcells(iTreg)peripherallygeneratedSubsetsofTregcellslTCRlCo-stimulationlCytokine-mediatedsignalsJosefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcellsMechanismsofTregcells-mediatedsuppressionpDirectlysuppressresponderFoxp3-Tcell
29、spIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppressionMajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,2009MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofF
30、oxp3-TcellsShevach.Immunity,2009Subsets“inthemaking”pFollicularhelperTcells(TFH)pTh9pTh22FollicularhelperTcells(TFH)PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcri
31、ptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemoryuVogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immunity29,138149(2008).uZaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinre
32、sponsetohelminthantigens.J.Exp.Med.206,991999(2009).uKingetal.IL-4-producingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.J.Exp.Med.206,10011007(2009).uRainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.Nature Immunol.10,385393(2009).Threestud
33、iesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedtotheBcellfolliclesuJohnstonetal.Bcl6andBlimp-1arereciprocalandan
34、tagonisticregulatorsofTfollicularhelpercelldifferentiation.Science325,10061010(2009).Th9uVeldhoen,M.et al.Transforminggrowthfactor-reprogramsthedifferentiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,13411346(2008).Th2cellscanchangeintoanIL-9-producingTcelltypeuNowak,E.
35、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-betainducesIL-9fromhumanTh17cells.JImmunol.2010uDuh
36、en,etal.Productionofinterleukin22butnotinterleukin17byasubsetofhumanskin-homingmemoryTcells.Nature Immunol.10,857863(2009).uTrifari,etal.IdentificationofahumanhelperTcellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17,TH1andTH2cells.Nature Immunol.10,864871(2009).Th22Inhuman
37、,butnotmouseExpressIL-22butnotIL-17orROR-t:Maypresentaskin-homingsubsetresponsibleforskininflammationsuchaspsoriasisApossiblehierarchyofstabilitypTheflexibilityofTcellsubsets?pWhataretheenvironmental(extrinsic)factorsthatallowforplasticity?pWhatregulateslineagecommitmentversusflexibility?pWhydoweneedsomanyfunctionalsubsets?Questions