T细胞亚群(最好的、漂亮免疫课件)电子版本.ppt

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1、T细胞亚群(最好的、漂亮免疫课件)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)调节性调节性CD4+T细胞细胞TCellsubsetsClassFunctionsAntigenreceptorandspecificityS

2、electedmarkersPercentoftotallymphocytes(human)TlymphocytesBloodLymphnodeSpleenCD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)Macrophageactivation(cell-mediatedimmunity)heterodimersDiversespecificitiesforpeptide-classIIMHCcomplexesCD3+,CD4+,CD8-50-60*50-6050-60CD8+cytotoxicTlymphocytesKil

3、lingofcellinfectedwithmicrobes,killingoftumorcellsheterodimersDiversespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunctionofotherTcells(regulationofimmuneresponses,maintenanceofself-tolerance)heterodimersCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesa

4、swell)Rare1010TlymphocytesHelperandcytotoxicfunctions(innateimmunity)heterodimersLimitedspecificitiesforpeptideandnonpeptideantigensCD3+,CD4,andCD8variableTcellsexpressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendritic

5、epidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstline

6、ofdefenseagainstarangeofpathogens.Jensen,K.D.et al.ThymicselectiondeterminesTcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferon Immunity29,90100(2008).pEpithelialTcellandPeripheralTcellpCD27-IL-17+TcellsandCD27+IFN-+TcellsSubsetsofTcellsDevelopmentalprogra

7、mmingofTcellsubsets.CuaDJ,etal.NaturereviewImmunology,2010uMartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321330(2009).TheyshowthatT-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfu

8、ngalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-17productioninTh17cells.uSutton,C.E.et al.Interleukin-1andIL-23induceinna

9、teIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.Immunity31,331341(2009).ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-17InnateActivationofIL-

10、17-ProductionbyaSpecializedTCellSubsetKapsenbergML.Immunity,2009uWitherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelialTcellactivation.Science2010SepIdentifyanepithelialTcells-specificcostimulatorymolecule,JAMLuPetermannF,etal.Tcellsenhanceautoimmunitybyrestrainingregu

11、latoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcellsinvivo.TwonewpapersaboutTCellpublishedinthismonthqNaveTcellsMatureTcellsthathavenotpr

12、eviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenqEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedqMemoryTcellsLong-lived,functi

13、onallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.NaiveTcellsEffectorTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferenti

14、allytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-SurfaceproteinexpressionHigh-affinityIL-2receptorLowHighLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)HighLowLoworvari

15、ableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmalluCentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionsw

16、hentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeuEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,especiallymucosa.produceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.Basedontheirhomingpropertiesandeffectorfunctions.SubsetsofmemoryTcell

17、sCD4+CD8+CD4+Th1-Th2hypothesis1986CoffmanandMossmanTh172006DiscoveryofCD4+ThcellsubsetsThesubsetsofCD4+ThcellsHowtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivateTh0qCytokinesStimulithatinfluencethepatternofThcelldifferentiationqHighdosesofantigenwithoutadjuvantsqDifferentsub

18、setsofdendriticcellsmayexistqThegeneticmakeupofthehostPropertiesofCD4+Th1andTh2subsetsDifferentiationofTh1SubsetvStimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcells Listeria,mycobacteriaandLeishmaniavImportantcytokinesfortheTh1differentiationvImportanttranscriptionfactors(TF)fo

19、rtheTh1differentiationIL-12IFN-IL-18typeIIFNs(inhuman)T-bet:masterregulatorSTAT4STAT1ThemolecularbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-beta

20、ndIFN-DifferentiationofTh1subsetsDifferentiationofTh2SubsetvImportantTFfortheTh2differentiationvStimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthandallergensvImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregu

21、latorSTAT6ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-3GATA-3qEnhancesexpressionoftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromoterso

22、fthesegenes2)causingchromatinremodelingqEnhancesitsownexpressionviaapositivefeedbackloopqBlocksTh1differentiationAmasterregulatorofTh2differentiationDevelopmentofTh2subsetsDevelopmentofTh1andTh2subsetsDifferentiationofTh17SubsetvStimulatedbyzymosan,fungus,myobacteriavImportantcytokinesfortheTh17diff

23、erentiationvImportanttranscriptionfactors(TF)fortheTh17differentiationIL-6TGF-IL-23IL-21ROR-t:masterregulatorROR-STAT3AhRTh17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.uVeldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunity

24、toenvironmentaltoxins.Nature453,106109(2008).uQuintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.Nature453,6571(2008).uKimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl.Acad.Sci.USA105,97219726(2008).uVeldhoen

25、,etal.NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009IMDMisbetterthan1640forTh17invitrodifferentiationThedifferentiationofTh17SubsetCD4+CD25+RegulatoryTcells(Tregcells)AsubsetofCD4+CD25+TcellsexpressingFoxp3Naturallypresentinimmu

26、nesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-toleranceuSakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995uHorietal.C

27、ontrolofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003uFontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTregpNaturalTregcells(nTreg)thymicderived,highlycontrolledbythymicmicroenvironmentpInducedTregcells(iTreg)per

28、ipherallygeneratedSubsetsofTregcellslTCRlCo-stimulationlCytokine-mediatedsignalsJosefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcellsMechanismsofTregcells-mediatedsuppressionpDirectlysuppressresponderFoxp3-TcellspIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAP

29、CMechanismsofTregcells-mediatedsuppressionMajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,2009MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,2009Subsets“inthemaking”pFollicularhelperTce

30、lls(TFH)pTh9pTh22FollicularhelperTcells(TFH)PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibo

31、diesandBcellmemoryuVogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immunity29,138149(2008).uZaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.206,991999(2009).uKingetal.IL-4-produ

32、cingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.J.Exp.Med.206,10011007(2009).uRainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.Nature Immunol.10,385393(2009).ThreestudiesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-ex

33、pressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedtotheBcellfolliclesuJohnstonetal.Bcl6andBlimp-1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldifferentiation.Science325,10

34、061010(2009).Th9uVeldhoen,M.et al.Transforminggrowthfactor-reprogramsthedifferentiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,13411346(2008).Th2cellscanchangeintoanIL-9-producingTcelltypeuNowak,E.C.et al.IL-9asamediatorofTh17-driveninflammatorydisease.J.Exp.Med.206,16

35、531660(2009).uElyaman,W.et al.IL-9inducesdifferentiationofTH17cellsandenhancesfunctionofFoxP3+naturalregulatoryTcells.Proc.Natl.Acad.Sci.USA106,1288512890(2009).uBeriouetal.TGF-betainducesIL-9fromhumanTh17cells.JImmunol.2010uDuhen,etal.Productionofinterleukin22butnotinterleukin17byasubsetofhumanskin

36、-homingmemoryTcells.Nature Immunol.10,857863(2009).uTrifari,etal.IdentificationofahumanhelperTcellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17,TH1andTH2cells.Nature Immunol.10,864871(2009).Th22Inhuman,butnotmouseExpressIL-22butnotIL-17orROR-t:Maypresentaskin-homingsubsetresponsibleforskininflammationsuchaspsoriasisApossiblehierarchyofstabilitypTheflexibilityofTcellsubsets?pWhataretheenvironmental(extrinsic)factorsthatallowforplasticity?pWhatregulateslineagecommitmentversusflexibility?pWhydoweneedsomanyfunctionalsubsets?Questions