Th1-and-Th2

Th1/Th2分化的调控机制授课教师：韩军艳主要内容T细胞亚群概述Th1/Th2亚群分化调控机制细胞因子转录因子STATTCR信号强弱表观遗传学调控RecognitionActivationproliferationDifferentiationmigrationEffectorfunctionMemoryApoptosisMaturationTCellBehaviorCD4+T细胞的活化（1）活化信号1(抗原识别信号)*双识别:TCR-肽/MHC-II*共受体:CD4-MHC-II*CD3传递特异性抗原识别信号（2）活化信号2(协同刺激信号)*B7-CD28等黏附分子结合（3）细胞因子(如IL-2等)*也是T细胞充分活化重要条件T细胞的增殖CD4+T细胞的分化活化T细胞表达多种细胞因子及受体T细胞克隆增殖分化为Th0Th1Th2IL-12,IFN-gIL-4IL-2+IL-2R•增殖分化为效应T细胞；•活化T细胞转变为记忆T细胞，参与再次应答；•活化T细胞发生凋亡，及时终止免疫应答。-活化诱导的细胞死亡（AICD）-被动细胞死亡（PCD）活化T细胞的转归TeTeTeTm活化T细胞的转归T细胞分类按对抗原的应答状态不同分类按TCR肽链组成分类按CD4和CD8表型分类按T细胞分泌的细胞因子谱分类按T细胞功能分类按对抗原应答的状态分类初始T细胞（naiveTcell,CD45RA+）效应T细胞(effectorTcell)记忆T细胞(memoryTcell,Tm，CD45RO+)按TCR肽链组成,CD4和CD8表型分类Th0细胞：属于naive细胞Th1细胞：IFN-g,参与细胞免疫应答（抵抗胞内感染）Th2细胞：IL-4,参与体液免疫应答（抵抗蠕虫、过敏反应）Tfh细胞：在淋巴滤泡辅助B细胞分化为浆细胞Th17细胞：IL-17,机体最早参与抗感染的细胞TREG细胞：属于抑制性T细胞亚群按CD4+T细胞分泌细胞因子谱的差异分类T细胞功能亚群调节网络EffectorfunctionsofTh1cellspCTLCTLLysisoftargetInductionofCTLdifferentiationIFN-gInflammatoryTh1TcellTh1MacrophageActivatedmacrophageKillingofintracellularbacteriaIL-12IFN-gIL-2Th1&Th2polarisationmaybeinfluencedbythetypeofinfectionIL-12IFN-gMacrophageNKcellIL-4MastcellTh1Th2Th0IFN-gCounterregulationofThcellsubsetsBalancedresponseTh2IFN-gIL-4--Th1Th2DominantTh1IL-4Th2-Th1DominantTh2Th1IFN-g-HumoralimmunityCellmediatedimmunityTh17细胞*指分泌IL-17的CD4+T细胞亚群，可促进炎症反应。分化与发育*DC等产生IL-6、IL-23→促进Th17细胞分化与发育表型IL-23R、CCR4、CCR6特征性核转录因子:RORγt生物学效应*招募中性粒细胞*促进多种细胞产生炎性细胞因子*促进细胞增殖IL-17表达调控*IL-23受体介导的信号转导→IL-17表达*IFN-γ、IL-4→抑制naiveT细胞表达IL-17T细胞的抑制性功能亚群CD4+CD25+Tr细胞(regulatorTcell,Treg)功能：抑制CD4+和CD8+T细胞增殖与功能分类：（1）天然调节性T细胞(nTreg)约占外周血CD4+T细胞的5%～10%（2）诱导性T细胞(iTreg)Tr1(由IL-10诱导产生)Th3(口服低剂量抗原诱导产生)CD4+T细胞的分化多样性Immunity.2009Mar20;30(3):324-35.Review.Th1Th2分化理论的提出TH1andTH2cells:differentpatternsoflymphokinesecretionleadtodifferentfunctionalproperties.MosmannTR,CoffmanRL.AnnuRevImmunol.1989;7:145-73.Review.Th1andTh2subsetsCytokinesplaycriticalrolesindifferentiationandeffectorfunctionsofTh1,Th2,andTh17cells.MasterTranscriptionFactorsTh1:T-betTh2:GATA3Th17:RORgtTreg：Foxp3LineagespecificTh2masterregulator:GATA3GATA3istheTh2masterregulator,wasthefirstmasterregulatortobeidentified.naiveCD4Tcellsexpressitatdetectablelevels.GATA3expressionisupregulatedordownregulatedduringTh2orTh1differentiation,respectively.ExpressionofretrovirallyencodedGATA3inTh1cellsmakesthesecellscompetenttoproduceIL-4andinducesendogenousGATA3production.Introducingadominant-negative(DN)formofGATA3inTcellsreducesTh2cytokineexpressionand,invivo,blocksinductionofairwayhypersensitivity.GATA3Th2differentiationistotallyabolishedinvitroandinvivointheabsenceofGATA3,asshownbythefailureofsuchdifferentiationinmiceinwhichGata3isdeletedinperipheralCD4Tcells.DeletingGata3fromfullydifferentiatedTh2cellsbytheintroductionofretrovirallyencodedCrehasonlyamodesteffectonIL-4productionbutcompletelyblockstheproductionofIL-5andIL-13,consistentwithdirectGATA3bindingtotheIL-5andIL-13promoters,butonlytoIL-4enhancers.InductionPhaseearlyIL-4productionPolarizationPhaseIL-4productionGATA3的其他功能GATA3isalsocriticalforthedevelopmentofCD4Tcells.GATA3promotesTh2differentiationthroughinstructingTh2commitment,selectivelystimulatingthegrowthofTh2cells,andsuppressingTh1differentiation.GATA3isalsoexpressedatintermediatelevelsinNKTcellsandTregcells.NKTcelldevelopmentandsurvivalisdefectiveinGata3conditionalknockoutmice,butthefunctionofGATA3inTregsisnotclear.Th1masterregulator:T-betT-betisamajorfactorforinducingIFN-γproductionandTh1celldifferentiation.OverexpressionofT-beteitherduringTh2differentiationorinfullydifferentiatedTh2cellscausessuchcellstoacquirecompetencetoproduceIFN-γwhile,atthesametime,suppressingtheircapacitytoproduceIL-4.T-betinducesIFN-γpartlythroughremodelingtheIfnggeneandbyupregulatingIL-12Rβ2expression,thuspromotingbothIFN-γexpressionandselectiveTh1cellexpansioninresponsetoIL-12.Tbx21−/−(T-betknockout)cellshaveseveredefectsinTh1celldifferentiationbothinvitroandinvivo.T-betIFN-γresponsestoLeishmaniamajoraresignificantlydiminished,althoughnotabolished,inTbx21−/−mice;thesemiceshowincreasedIL-4andIL-5productioninresponsetoL.majorinfection.Notably,Tbx21+/−cellsdisplayapartialphenotype.T-bet-expressingCD4Tcellsaredramaticallyreducedinhumanasthmaticairways,andTbx21−/−micespontaneouslydevelopairwayhypersensitivity.ThedifferentialrequirementforT-betforIFN-γproductionbyCD4andCD8TcellsmaybeexplainedbytheheightenedexpressionofanotherT-boxfamilymember,Eomesodermin(Eomes),inCD8Tcells.RoleofT-betinTH1celldifferentiationSignalingTransducerandActivatorofTranscription(STAT)ProteinsSTAT1—ActivationofSTAT1byIFN-γisimportantfortheinductionofT-betduringinvitroTh1differentiation.IFN-γ,throughSTAT1activation,alsoinducesT-betexpressioninmonocytes,macrophages,DCs,andBcells.TheexistenceofapositivefeedbackloopinwhichIFN-γ,actingthroughT-bet,inducesmoreIFN-γindicatesthatSTAT1servesasacriticalmediatorfortheamplificationofinvitroTh1responses.However,intheacutephaseofToxoplasmagondiiinfectioninmice,theappearanceofCD4TcellscapableofproducingIFN-γdoesnotrequireSTAT1.S