Th1 Th2 表面标志.ppt

Thelpersubsets,PennyMorelMarch23,20074-0343,,Outline,ThcellsubsetsRoleofDCsindeterminingTcelleffectorfunctionFactorsnecessaryforTh1/2differentiationAnewThsubset-ThIL-17DevelopmentandfunctionofTreginperiphery,NaveCD4+TcellscandifferentiateintoseveralTeffandTregtypes,Immunol.Rev.182:207,2001,Th1/Th2/Th17indisease,Agent/DiseaseHostResponseOutcomeLeishmaniasisMTh1CureTh2ExacerbationLeprosyHTh1TuberculoidTh2LepromatousRA/MSHTh1Th1cellsinlesionHTh17Th17inlesionsAllergyHTh2Th2cytokinesinlesionMTh17InducesPMNAcGVHDMTh1Th1cytokinesChrGVHDMTh2Th2cytokines,NatureRev.Immunol.3:984,2003,DendriticcellsandTcelleffectorfunction,Th1/Th2differentiation,ArisefromacommonprecursorCytokinesAntigendoseCostimulatorymoleculesDifferentiationresultsinexpressionofmasterregulators:GATA-3forTh2andT-betforTh1,SignalingmoleculesandtranscriptionfactorsimportantinTh1/Th2differentiationAnnu.RevImmunol.21:713,2003,KnockoutmicethathavedefectsinTh1development:IFN-,IFN-R,IL-12,IL-12R,Stat4,IRF-1,ICSBP,T-betIL-12isnecessaryforIFN-production,andIFN-isnecessaryfortheinductionofIL-12responsiveness(actsviainductionofT-bet)stimulatesexpressionoftheIL-12Rchain(signaltransduction)IL-4andIFN-aremutuallyantagonisticinTh1/Th2developmentSourceofIL-12:dendriticcells,macrophages.CertainpathogensstimulatesecretionoflargeamountsofIL-12byDCandmacrophagesSourceofIFN-:NKcells,Th1cells,KnockoutmicethathavedefectsinTh2development:IL-4,IL-13,IL-4R,Stat6GATA-3antisenseblocksTh2developmentSourceofIL-4WasthoughttobeeithermastcellsorCD4+NK1.1+Tcells-butneitheronewasprovenNowthoughttocomefromdevelopingTh2cells-undertheinfluenceofIL-6,althoughIL-6KOmicecanstillmakesomeTh2responses.ItispossiblethatTh2differentiationisthedefaultpathwayintheabsenceofIL-12,CytokinesinfluenceTh1/Th2differentiation,Science260:547,1993,Interleukin4,20kDproteinproducedbyTh2cells,mastcells,NKTcellsInducesproliferationofTcellsanddifferentiationofTh2cells;antagonizesTh1differentiationInducestheexpressionofGATA-3transcriptionfactor,IL-4receptor,Annu.Rev.Immunol17:701,1999,Stat6,Interleukin-12,HeterodimericcytokineIL-12p70-formedbytwochainsIL-12p40andIL-12p35(encodedondifferentchromosomes)ProducedbyactivatedDC,macrophagesActsonNKandTcellstostimulateIFN-production;costimulatesTh1proliferation;enhancesNKcytotoxicactivity;inducesTh1differentiationIL12-Rhastwochainsand2;signalsthroughstat4IL-12p40canformhomodimersandinhibittheactionofIL-12p70,IL-12andIL-23,ThIL-17cells,ProduceIL-17,IL-17F,IL-6,TNFIL-17inducestheproductionproinflammatorycytokines:TNF,IL-1,IL-6,IL-8ThIL-17cellshavebeenfoundinthediseasedtissuesofpatientswithRA,Lymearthritis,MS,SLEandasthmaNewdatasuggestthatthisisadistinctlineage-developmentmayrequireIL-6andTGF-,CytokinerequirementsforThIL-17,Nature44:235(2006),Annu.Rev.Immunol.1997.15:297-322.,AntigendoseinfluencesTh1/Th2developmentVeryhighandverylowdoseleadstoTh2responseIntermediatedoseleadstoTh1responseSamepatternisnotalwaysseenincomplexantigens,RoleofDCsubsetsandantigendoseinthedifferentiationofTh1orTh2cellsJ.ExpMed.197:101.2003,OthermoleculesimplicatedinTh1/Th2differentiation,Costimulatorymolecules:CD86,B7-hbindtoCD28andICOSresp.OX40(Tcell)-OX40L(DC)-inducedafteractivation,favorTh2Chemokines-differentialexpressionofchemokinereceptorsofTcellsubsets,differentpatternsofchemokineproductionbyDCsubsets,NewdatasuggestthatOX40Lmayplayaroleininducinginflammatorycytokines(TNF)J.Exp.Med.202:1213.2005,RegulatoryTcellsintheperiphery,NaturallyoccurringCD4+CD25+Tregs;developinthymusTr1cells-produceIL-10;inducedfollowinginteractionwithDCinpresenceofimmunsuppressivecytokinesTh3cells-produceIL-10andTGF-b,usuallyfoundatmucosalsurfaces,J.Immunol.171:6323,2003,MechanismsofSuppression,Alsoin