復(fù)旦大學(xué)課件T細(xì)胞亞群1017

T細(xì)胞亞群何睿ruihe@免疫學(xué)系上海醫(yī)學(xué)院復(fù)旦大學(xué)1精品PPT|借鑒參考第一頁，共五十四頁。2精品PPT|借鑒參考第二頁，共五十四頁。3精品PPT|借鑒參考第三頁，共五十四頁。Classesoflymphocytes4精品PPT|借鑒參考第四頁，共五十四頁。T細(xì)胞亞群T細(xì)胞活化分子機(jī)制T細(xì)胞免疫應(yīng)答及其效應(yīng)

自身免疫和超敏反應(yīng)5精品PPT|借鑒參考第五頁，共五十四頁。Tcellsubsets

Tcellsand

TcellsCD4+TcellsandCD8+T

Na?veTcells（初始T細(xì)胞）EffectorTcells（效應(yīng)T細(xì)胞）MemoryTcells（記憶T細(xì)胞）

Thelper(Th)輔助性CD4+T細(xì)胞CytotoxicTcells(CTLs)細(xì)胞毒性CD8+T細(xì)胞RegulatoryTcells(Tregs)調(diào)節(jié)性CD4+T細(xì)胞6精品PPT|借鑒參考第六頁，共五十四頁。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

7精品PPT|借鑒參考第七頁，共五十四頁。

TcellsexpressalimitednumberofTCRsabundantinepithelialtissuesofcertainspecies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted.maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.8精品PPT|借鑒參考第八頁，共五十四頁。Jensen,K.D.etal.

Thymicselectiondetermines

Tcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferon

Immunity29,90–100(2008).

Epithelial

TcellandPeripheral

Tcell

CD27-IL-17+

TcellsandCD27+IFN-

+

Tcells

SubsetsofTcells

9精品PPT|借鑒參考第九頁，共五十四頁。Developmentalprogrammingof

Tcellsubsets.CuaDJ,etal.NaturereviewImmunology,201010精品PPT|借鑒參考第十頁，共五十四頁。

MartinBetal.IL-17-Producing

TcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.

Immunity31,321–330(2009).

Theyshowthat

T-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecognizearchetypicalandfungalconstituents.These

T-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.Oneoftherolesof

T-17-derivedmaybeindirectordirectamplificationofIL-17productioninTh17cells.

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

Tcells,amplifyingTh17responsesandautoimmunity.Immunity31,331–341(2009).

Thisreportshowsthat

TcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-1711精品PPT|借鑒參考第十一頁，共五十四頁。InnateActivationofIL-17-ProductionbyaSpecialized

TCellSubsetKapsenbergML.Immunity,200912精品PPT|借鑒參考第十二頁，共五十四頁。Witherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelial

Tcellactivation.Science2010SepIdentifyanepithelial

Tcells-specificcostimulatorymolecule,JAMLPetermannF,etal.

TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcellsinvivo.Twonewpapersabout

TCellpublishedinthismonth13精品PPT|借鑒參考第十三頁，共五十四頁。14精品PPT|借鑒參考第十四頁，共五十四頁。Na?veTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.15精品PPT|借鑒參考第十五頁，共五十四頁。NaiveTcellsEffectorTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferentiallytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-Surfaceproteinexpression

High-affinityIL-2receptorLowHighLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)HighLowLoworvariableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmall16精品PPT|借鑒參考第十六頁，共五十四頁。CentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallengeEffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,especiallymucosa.produceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.Basedontheir

homingpropertiesandeffectorfunctions.SubsetsofmemoryTcells

17精品PPT|借鑒參考第十七頁，共五十四頁。CD4+CD8+CD4+18精品PPT|借鑒參考第十八頁，共五十四頁。Th1-Th2hypothesis1986CoffmanandMossmanTh172006DiscoveryofCD4+Thcellsubsets19精品PPT|借鑒參考第十九頁，共五十四頁。ThesubsetsofCD4+ThcellsHowtheyareinduced,WhatcytokinestheyproduceWhateffectormechanismstheyactivate

Th020精品PPT|借鑒參考第二十頁，共五十四頁。

CytokinesStimulithatinfluencethepatternofThcelldifferentiationHighdosesofantigenwithoutadjuvantsDifferentsubsetsofdendriticcellsmayexistThegeneticmakeupofthehost21精品PPT|借鑒參考第二十一頁，共五十四頁。PropertiesofCD4+Th1andTh2subsets22精品PPT|借鑒參考第二十二頁，共五十四頁。DifferentiationofTh1Subset

StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcellsListeria,mycobacteriaandLeishmaniaImportantcytokinesfortheTh1differentiation

Importanttranscriptionfactors(TF)fortheTh1differentiation

IL-12

IFN-

IL-18typeIIFNs(inhuman)

T-bet:masterregulatorSTAT4STAT123精品PPT|借鑒參考第二十三頁，共五十四頁。ThemolecularbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-

andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4

IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-

24精品PPT|借鑒參考第二十四頁，共五十四頁。DifferentiationofTh1subsets25精品PPT|借鑒參考第二十五頁，共五十四頁。DifferentiationofTh2SubsetImportantTFfortheTh2differentiation

StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivation

Helminthandallergens

ImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregulatorSTAT626精品PPT|借鑒參考第二十六頁，共五十四頁。ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6

AgrecognitionbyTCRGATA-327精品PPT|借鑒參考第二十七頁，共五十四頁。PPT內(nèi)容概述T細(xì)胞亞群。ruihe@。Na?veTcells（初始T細(xì)胞）。CD3+,CD4-,CD8+。KapsenbergML.Immunity,2009。Na?veTcells。T-bet:masterregulator。GATA-3:masterregulator。ROR-t:masterregulator。Shevach.Immunity,2009。53第二十八頁，共五十四頁。GATA-3EnhancesexpressionoftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodelingEnhancesitsownexpressionviaapositivefeedbackloopBlocksTh1differentiationAmasterregulatorofTh2differentiation

29精品PPT|借鑒參考第二十九頁，共五十四頁。DevelopmentofTh2subsets30精品PPT|借鑒參考第三十頁，共五十四頁。DevelopmentofTh1andTh2subsets31精品PPT|借鑒參考第三十一頁，共五十四頁。32精品PPT|借鑒參考第三十二頁，共五十四頁。DifferentiationofTh17Subset

Stimulatedbyzymosan,fungus,myobacteriaImportantcytokinesfortheTh17differentiation

Importanttranscriptionfactors(TF)fortheTh17differentiation

IL-6

TGF-

IL-23

IL-21

ROR-

t:masterregulator

ROR-

STAT3

AhR33精品PPT|借鑒參考第三十三頁，共五十四頁。Th17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.Veldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.

Nature

453,106–109(2008).Quintanaetal.ControlofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.

Nature

453,65–71(2008).Kimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl.Acad.Sci.USA

105,9721–9726(2008).Veldhoen,etal.NaturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009

IMDMisbetterthan1640forTh17invitrodifferentiation34精品PPT|借鑒參考第三十四頁，共五十四頁。ThedifferentiationofTh17Subset35精品PPT|借鑒參考第三十五頁，共五十四頁。CD4+CD25+RegulatoryTcells(Tregcells)AsubsetofCD4+CD25+TcellsexpressingFoxp3

Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-tolerance36精品PPT|借鑒參考第三十六頁，共五十四頁。Sakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995Horietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003Fontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTreg37精品PPT|借鑒參考第三十七頁，共五十四頁。NaturalTregcells(nTreg)

thymicderived,highlycontrolledbythymicmicroenvironmentInducedTregcells(iTreg)

peripherallygeneratedSubsetsofTregcells

38精品PPT|借鑒參考第三十八頁，共五十四頁。TCRCo-stimulationCytokine-mediatedsignals39精品PPT|借鑒參考第三十九頁，共五十四頁。Josefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcells40精品PPT|借鑒參考第四十頁，共五十四頁。MechanismsofTregcells-mediatedsuppression

41精品PPT|借鑒參考第四十一頁，共五十四頁。DirectlysuppressresponderFoxp3-TcellsIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppression

42精品PPT|借鑒參考第四十二頁，共五十四頁。MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,200943精品PPT|借鑒參考第四十三頁，共五十四頁。MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,200944精品PPT|借鑒參考第四十四頁，共五十四頁。45精品PPT|借鑒參考第四十五頁，共五十四頁。Subsets“inthemaking”FollicularhelperTcells(TFH)Th9Th2246精品PPT|借鑒參考第四十六頁，共五十四頁。FollicularhelperTcells(TFH)PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory47精品PPT|借鑒參考第四十七頁，共五十四頁。Vogelzang,etal.GenerationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.

Immunity

29,138–149(2008).Zaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.

206,991–999(2009).Kingetal.IL-4-producingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.

J.Exp.Med.

206,1001–1007(2009).Rainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.NatureImmunol.

10,385–393(2009).ThreestudiesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedtotheBcellfolliclesJohnstonetal.Bcl6andBlimp-1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldifferentiation.Science

325,1006–1010(2009).48精品PPT|借鑒參考第四十八頁，共五十四頁。Th9Veldhoen,M.etal.Tra