分子免疫学T细胞亚群.ppt

,T细胞亚群T细胞活化机制T细胞免疫应答及其效应,PhasesofTcellresponses,priming,Tcellsubsets,Tcells(95%)andTcells(5%)CD4+TcellsandCD8+TcellsNaveTcells（初始T细胞）EffectorTcells（效应T细胞）MemoryTcells（记忆T细胞）Thelper(Th)辅助性CD4+T细胞CytotoxicTcells(CTLs)细胞毒性CD8+T细胞RegulatoryTcells(Tregs)调节性CD4+T细胞,TCellsubsets,Positiveselection,Negativeselection,Tcelldevelopmentinthethymus,PhasesofTcellresponses,priming,NaveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector),BasedonthehistoryofantigenencounterandthestageofTcellactivation.,CentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,duceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.,Basedontheirhomingpropertiesandeffectorfunctions.,SubsetsofmemoryTcells,NatureImmunol,2011,June,thereviewsofmemoryTcell,CD4+,CD8+,CD4+,.,EffectorTcellsubsets,Th1-Th2hypothesis1986CoffmanandMossmanTh172005Tfh2000,DiscoveryofCD4+Thcellsubsets,Howtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivate,Th0,Th1,Th2,Th17,HumoralImmunity,Immunemodulation,ThesubsetsofCD4+Thcells,PropertiesofCD4+Th1andTh2subsets,Cytokines,StimulithatinfluencethepatternofThcelldifferentiation,TCRsignalstrengthDifferentsubsetsofdendriticcellsmayexistThegeneticmakeupofthehost,STAT:Signaltransducerandactivatoroftranscription,DifferentiationofTh1Subset,StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcellsListeria,mycobacteriaandLeishmania,ImportantcytokinesfortheTh1differentiation,Importanttranscriptionfactors(TF)fortheTh1differentiation,IL-12IFN-IL-18typeIIFNs(inhuman),T-bet:masterregulatorSTAT4STAT1,ThemolecularbasisofTh1differentiation,TheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4,IL-12STAT-4IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-,DifferentiationofTh2Subset,ImportantTFfortheTh2differentiation,StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivationHelminthandallergens,ImportantcytokinesfortheTh2differentiation,IL-4,GATA-3:masterregulatorSTAT6,ThemolecularbasisofTh2differentiation,TheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6,Th2differentiationismostdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-3,DevelopmentofTh1andTh2subsets,Th2celldifferentiationrequiresbothGATA3expressionandSTAT5activation,NatureReviewImmunol,2010,DifferentiationofTh17Subset,Stimulatedbyzymosan,fungus,myobacteria,ImportantcytokinesfortheTh17differentiation,Importanttranscriptionfactors(TF)fortheTh17differentiation,IL-6TGF-IL-23IL-21,ROR-t:masterregulatorROR-STAT3AhR,StepsinthedifferentiationofTh17cells,ConventionalTh17celldevelopment,ImmunologicReview,2013,FollicularhelperTcells(TFH),PreferentiallyresidentinBcellfolliclesExpressCXCR5,aearlydefiningmarkerProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory,AnatomicallocalizationandcellularrequirementsforTfhcellgeneration,JEM,2012,JEM,2012,AnatomicallocalizationandcellularrequirementsforTfhcellgeneration,CD4+CD25+RegulatoryTcells(Tregcells),AsubsetofCD4+CD25+TcellsexpressingFoxp3Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-tolerance,Sakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995,TheDiscoveryofCD4+CD25+Tregcells,IdentifyCD25asasurfacemarker,ThediscoveryofFoxp3anditsroleinCD4+CD25+Treg,Horietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003Fontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003R.Khattri,etal,AnessentialroleforScurfininCD4+CD25+Tregulatorycells,Nat.Immunol.4(2003),pp.337342.,NaturalTregcells(nTreg)Thymicderived,highlycontrolledbythymicmicroenvironmentInducedTregcells(iTreg)PeripherallygeneratedfromFoxp3-CD4+Tcellsdifferentiatedundermorevariedconditions,SubsetsofTregcells,ThymicandPeripheralGenerationofFoxp3+TregCells,TCRCo-stimulationCytokine-mediatedsignals,MechanismsofiTregcellsdifferentiation,TCRTGF-IL-2,NonregulatorynaveconventionalCD4+TcellsareabletoacquireFoxp3expressionandregulatoryfunction.TheconversioncanoccurinbothinvitroandinvivoTregcellsconvertedinvivocanbefunctionallyquiteeffective,Subsets“inthemaking”,Th9Th22,Th9,Veldhoen,M.etal.Transforminggrowthfactor-reprogramsthedifferentiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,13411346(2008).Th2cellscanchangeintoanIL-9-producingTcelltypeNowak,E.C.etal.IL-9asamediatorofTh17-driveninflammatorydisease.J.Exp.Med.206,16531660(2009).Elyaman,W.etal.IL-9inducesdifferentiationofTH17cellsandenhancesfunctionofFoxP3+naturalregulatoryTcells.Proc.Natl.Acad.Sci.USA106,1288512890(2009).Beriouetal.TGF-betainducesIL-9fromhumanTh17cells.JImmunol.2010,Duhen,etal.Productionofinterleukin22butnotinterleukin17byasubsetofhumanskin-homingmemoryTcells.NatureImmunol.10,857863(2009).Trifari,etal.IdentificationofahumanhelperTcellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17,TH1andTH2cells.NatureImmunol.10,864871(2009).,Th22,Inhuman,butnotmouseExpressIL-22butnotIL-17orROR-tMaypresentaskin-homingsubsetresponsibleforskininflammationsuchaspsoriasis,JEM,2012,CD4+Tcellflexibility,Apossiblehierarchyofstability,TGFandIL-6gradientsregulateearlyTh17,iTreg,andTh22commitment,TheflexibilityofTcellsubsets?Whataretheenvironmental(extrinsic)factorsthatallowforplasticity?Whatregulateslineagecommitmentversusflexibility?Whydoweneedsomanyfunctionalsubsets?,Questions?,InnateTcells,Tcells,expressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.,SixofthebestTcellfunctions,NatureReviewImmunol,2013,MartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321330(2009).TheyshowthatT-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-