T细胞亚群医学知识专家讲座

T细胞亚群何睿ruihe@免疫学系上海医学院复旦大学T细胞亚群医学知识专家讲座第1页T细胞亚群医学知识专家讲座第2页T细胞亚群医学知识专家讲座第3页ClassesoflymphocytesT细胞亚群医学知识专家讲座第4页T细胞亚群T细胞活化分子机制T细胞免疫应答及其效应

本身免疫和超敏反应T细胞亚群医学知识专家讲座第5页TcellsubsetsTcellsandTcellsCD4+TcellsandCD8+T

NaïveTcells（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)调整性CD4+T细胞T细胞亚群医学知识专家讲座第6页TCellsubsetsClassFunctionsAntigenreceptorandspecificitySelectedmarkersPercentoftotallymphocytes(human)αβTlymphocytes

BloodLymphnodeSpleen

CD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)

Macrophageactivation(cell-mediatedimmunity)αβheterodimers

Diversespecificitiesforpeptide-classIIMHCcomplexesCD3+,CD4+,CD8-50-60*50-6050-60

CD8+cytotoxicTlymphocytesKillingofcellinfectedwithmicrobes,killingoftumorcellsαβheterodimers

Diversespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunctionofotherTcells(regulationofimmuneresponses,maintenanceofself-tolerance)αβheterodimersCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesaswell)Rare1010γδTlymphocytesHelperandcytotoxicfunctions(innateimmunity)γδheterodimers

LimitedspecificitiesforpeptideandnonpeptideantigensCD3+,CD4,andCD8variable

T细胞亚群医学知识专家讲座第7页TcellsexpressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.T细胞亚群医学知识专家讲座第8页Jensen,K.D.etal.

Thymicselectiondetermines

Tcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferonImmunity29,90–100().

Epithelial

TcellandPeripheral

Tcell

CD27-IL-17+TcellsandCD27+IFN-+Tcells

SubsetsofTcells

T细胞亚群医学知识专家讲座第9页Developmentalprogrammingof

Tcellsubsets.CuaDJ,etal.NaturereviewImmunology,T细胞亚群医学知识专家讲座第10页

MartinBetal.IL-17-Producing

TcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.

Immunity31,321–330().

TheyshowthatT-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfungalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-17productioninTh17cells.

Sutton,C.E.etal.Interleukin-1andIL-23induceinnateIL-17productionfrom

Tcells,amplifyingTh17responsesandautoimmunity.Immunity31,331–341().

ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-17T细胞亚群医学知识专家讲座第11页InnateActivationofIL-17-ProductionbyaSpecializedTCellSubsetKapsenbergML.Immunity,T细胞亚群医学知识专家讲座第12页Witherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelial

Tcellactivation.ScienceSepIdentifyanepithelialTcells-specificcostimulatorymolecule,JAMLPetermannF,etal.

TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcellsinvivo.TwonewpapersaboutTCellpublishedinthismonthT细胞亚群医学知识专家讲座第13页T细胞亚群医学知识专家讲座第14页NaïveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.T细胞亚群医学知识专家讲座第15页NaiveTcellsEffectorTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferentiallytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-Surfaceproteinexpression

High-affinityIL-2receptorLowHighLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)HighLowLoworvariableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmallT细胞亚群医学知识专家讲座第16页CentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,duceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.Basedontheir

homingpropertiesandeffectorfunctions.SubsetsofmemoryTcells

T细胞亚群医学知识专家讲座第17页CD4+CD8+CD4+T细胞亚群医学知识专家讲座第18页Th1-Th2hypothesis1986CoffmanandMossmanTh17DiscoveryofCD4+ThcellsubsetsT细胞亚群医学知识专家讲座第19页ThesubsetsofCD4+ThcellsHowtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivate

Th0T细胞亚群医学知识专家讲座第20页

CytokinesStimulithatinfluencethepatternofThcelldifferentiationHighdosesofantigenwithoutadjuvantsDifferentsubsetsofdendriticcellsmayexistThegeneticmakeupofthehostT细胞亚群医学知识专家讲座第21页PropertiesofCD4+Th1andTh2subsetsT细胞亚群医学知识专家讲座第22页DifferentiationofTh1Subset

StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcellsListeria,mycobacteriaandLeishmaniaImportantcytokinesfortheTh1differentiation

Importanttranscriptionfactors(TF)fortheTh1differentiation

IL-12

IFN-IL-18typeIIFNs(inhuman)

T-bet:masterregulatorSTAT4STAT1T细胞亚群医学知识专家讲座第23页ThemolecularbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4

IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-T细胞亚群医学知识专家讲座第24页DifferentiationofTh1subsetsT细胞亚群医学知识专家讲座第25页DifferentiationofTh2SubsetImportantTFfortheTh2differentiation

StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivation

Helminthandallergens

ImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregulatorSTAT6T细胞亚群医学知识专家讲座第26页ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6

AgrecognitionbyTCRGATA-3T细胞亚群医学知识专家讲座第27页GATA-3EnhancesexpressionoftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodelingEnhancesitsownexpressionviaapositivefeedbackloopBlocksTh1differentiationAmasterregulatorofTh2differentiation

T细胞亚群医学知识专家讲座第28页DevelopmentofTh2subsetsT细胞亚群医学知识专家讲座第29页DevelopmentofTh1andTh2subsetsT细胞亚群医学知识专家讲座第30页T细胞亚群医学知识专家讲座第31页DifferentiationofTh17Subset

Stimulatedbyzymosan,fungus,myobacteriaImportantcytokinesfortheTh17differentiation

Importanttranscriptionfactors(TF)fortheTh17differentiation

IL-6

TGF-IL-23

IL-21

ROR-t:masterregulator

ROR-

STAT3

AhRT细胞亚群医学知识专家讲座第32页Th17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.Veldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.

Nature

453,106–109().Quintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.

Nature

453,65–71().Kimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl.Acad.Sci.USA

105,9721–9726().Veldhoen,etal.NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,

IMDMisbetterthan1640forTh17invitrodifferentiationT细胞亚群医学知识专家讲座第33页ThedifferentiationofTh17SubsetT细胞亚群医学知识专家讲座第34页CD4+CD25+RegulatoryTcells(Tregcells)AsubsetofCD4+CD25+TcellsexpressingFoxp3

Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-toleranceT细胞亚群医学知识专家讲座第35页Sakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995Horietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.ScienceFontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunolLandmarkpapersaboutTregT细胞亚群医学知识专家讲座第36页NaturalTregcells(nTreg)

thymicderived,highlycontrolledbythymicmicroenvironmentInducedTregcells(iTreg)

peripherallygeneratedSubsetsofTregcells

T细胞亚群医学知识专家讲座第37页TCRCo-stimulationCytokine-mediatedsignalsT细胞亚群医学知识专家讲座第38页Josefowiczetal.Immunity,DifferentiationofthymicandinducedTregcellsT细胞亚群医学知识专家讲座第39页MechanismsofTregcells-mediatedsuppression

T细胞亚群医学知识专家讲座第40页DirectlysuppressresponderFoxp3-TcellsIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppression

T细胞亚群医学知识专家讲座第41页MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,T细胞亚群医学知识专家讲座第42页MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,T细胞亚群医学知识专家讲座第43页T细胞亚群医学知识专家讲座第44页Subsets“inthemaking”FollicularhelperTcells(TFH)Th9Th22T细胞亚群医学知识专家讲座第45页FollicularhelperTcells(TFH)PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemoryT细胞亚群医学知识专家讲座第46页Vogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.

Immunity

29,138–149().Zaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.

206,991–999().Kingetal.IL-4-producingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.

J.Exp.Med.

206,1001–1007().Rainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.NatureImmunol.

10,385–393().ThreestudiesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedto