ThTh表面標(biāo)志專題知識(shí)專家講座

ThelpersubsetsPennyMorelMarch23,2023OutlineThcellsubsetsRoleofDCsindeterminingTcelleffectorfunctionFactorsnecessaryforTh1/2differentiationAnewThsubset-ThIL-17DevelopmentandfunctionofTreginperipheryNa?veCD4+TcellscandifferentiateintoseveralTeffandTregtypesImmunol.Rev.182:207,2023Th1/Th2/Th17indiseaseAgent/Disease Host Response OutcomeLeishmaniasis M Th1 Cure Th2 ExacerbationLeprosy H Th1 Tuberculoid Th2 LepromatousRA/MS H Th1 Th1cellsinlesion H Th17 Th17inlesions Allergy H Th2 Th2cytokinesin lesion M Th17 InducesPMNAcGVHD M Th1 Th1cytokinesChrGVHD M Th2 Th2cytokinesNatureRev.Immunol.3:984,2023DendriticcellsandTcelleffectorfunctionTh1/Th2differentiationArisefromacommonprecursorCytokinesAntigendoseCostimulatorymoleculesDifferentiationresultsinexpressionofmasterregulators:GATA-3forTh2andT-betforTh1SignalingmoleculesandtranscriptionfactorsimportantinTh1/Th2differentiationAnnu.RevImmunol.21:713,2023KnockoutmicethathavedefectsinTh1development: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/Th2development

SourceofIL-12:dendriticcells,macrophages.CertainpathogensstimulatesecretionoflargeamountsofIL-12byDCandmacrophagesSourceofIFN-:NKcells,Th1cellsKnockoutmicethathavedefectsinTh2development:IL-4,IL-13,IL-4R,Stat6GATA-3antisenseblocksTh2developmentSourceofIL-4WasthoughttobeeithermastcellsorCD4+NK1.1+Tcells-butneitheronewasprovenNowthoughttocomefromdevelopingTh2cells-undertheinfluenceofIL-6,althoughIL-6KOmicecanstillmakesomeTh2responses.ItispossiblethatTh2differentiationisthedefaultpathwayintheabsenceofIL-12CytokinesinfluenceTh1/Th2differentiationScience260:547,1993Interleukin420kDproteinproducedbyTh2cells,mastcells,NKTcellsInducesproliferationofTcellsanddifferentiationofTh2cells;antagonizesTh1differentiationInducestheexpressionofGATA-3transcriptionfactorIL-4receptorAnnu.Rev.Immunol17:701,1999Stat6Interleukin-12HeterodimericcytokineIL-12p70-formedbytwochainsIL-12p40andIL-12p35(encodedondifferentchromosomes)ProducedbyactivatedDC,macrophagesActsonNKandTcellstostimulateIFN-production;costimulatesTh1proliferation;enhancesNKcytotoxicactivity;inducesTh1differentiationIL12-Rhastwochainsand2;signalsthroughstat4IL-12p40canformhomodimersandinhibittheactionofIL-12p70IL-12andIL-23ThIL-17cellsProduceIL-17,IL-17F,IL-6,TNFIL-17inducestheproductionproinflammatorycytokines:TNF,IL-1,IL-6,IL-8ThIL-17cellshavebeenfoundinthediseasedtissuesofpatientswithRA,Lymearthritis,MS,SLEandasthmaNewdatasuggestthatthisisadistinctlineage-developmentmayrequireIL-6andTGF-

CytokinerequirementsforThIL-17Nature44:235(2023)

Annu.Rev.Immunol.1997.15:297-322.AntigendoseinfluencesTh1/Th2developmentVeryhighandverylowdoseleadstoTh2responseIntermediatedoseleadstoTh1responseSamepatternisnotalwaysseenincomplexantigensRoleofDCsubsetsandantigendoseinthedifferentiationofTh1orTh2cellsJ.ExpMed.197:101.2023OthermoleculesimplicatedinTh1/Th2differentiationCostimulatorymolecules:CD86,B7-hbindtoCD28andICOSresp.OX40(Tcell)-OX40L(DC)-inducedafteractivation,favorTh2Chemokines-differentialexpressionofchemokinereceptorsofTcellsubsets,differentpatternsofchemokineproductionbyDCsubsetsNewdatasuggestthatOX40Lmayplayaroleininducinginflammatorycytokines(TNF)J.Exp.Med.202:1213.2023RegulatoryTcellsintheperipheryNaturallyoccurringCD4+CD25+Tregs;developinthymusTr1cells-produceIL-10;inducedfollowinginteractionwithDCinpresenceofimmunsuppressivecytokinesTh3cells-produceIL-10andTGF-b,usuallyfoundatmucosalsurfacesJ.Immunol.171:6323,2023MechanismsofSuppressionAlsoi