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Classesoflymphocytes❖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❖自身免疫和超敏反应❖Tcellsubsets❑TcellsandTcells❑CD4+TcellsandCD8+T❑NaïveTcells（初始T细胞）Effect

orTcells（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TCellsubsetsClassFunctionsAntigenreceptorandspecificitySelectedmarkersPercentoftotallymphocyte

s(human)αβTlymphocytesBloodLymphnodeSpleenCD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)Macrophageactivati

on(cell-mediatedimmunity)αβheterodimersDiversespecificitiesforpeptide-classIIMHCcomplexesCD3+,CD4+,CD8-50-60*50

-6050-60CD8+cytotoxicTlymphocytesKillingofcellinfectedwithmicrobes,killingoftumorcellsαβheterodimersDive

rsespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunctionofot

herTcells(regulationofimmuneresponses,maintenanceofself-tolerance)αβheterodimersCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesaswell)Rare

1010γδTlymphocytesHelperandcytotoxicfunctions(innateimmunity)γδheterodimersLimitedspecificitiesforpeptideandnonpeptide

antigensCD3+,CD4,andCD8variableTcells➢expressalimitednumberofTCRs➢abundantinepithelialtissuesofcertainspecies:inthesmallbowe

lmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)➢donotrecognizeMHC-associatedpeptideantigensandarenotMHCrestricted

.➢maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suchasmicrobialheatshockproteins.➢mayrepr

esentanimportantbridgebetweeninnateandadaptiveimmunity,functioningaslymphocytesthatenhancethefirstlineofdefenseagainstarang

eofpathogens.Jensen,K.D.etal.ThymicselectiondeterminesTcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakei

nterferonImmunity29,90–100(2008).EpithelialTcellandPeripheralTcellCD27-IL-17+TcellsandCD27+IFN-+Tcell

sSubsetsofTcellsDevelopmentalprogrammingofTcellsubsets.CuaDJ,etal.NaturereviewImmunology,2010◆Ma

rtinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.Immunity31,321–330(2009).TheyshowthatT-

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

TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derivedIL-23andtobacteriaandfungiwitho

utconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-17productioninTh17cells.◆Sutton,C.E.etal.Inter

leukin-1andIL-23induceinnateIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.Immunity31,331–341(2009).Thisr

eportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-spec

ificTh17cells.AmajorinnatesourceofIL-17InnateActivationofIL-17-ProductionbyaSpecializedTCellSubsetKapsenbergM

L.Immunity,2009◆Witherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelialTcella

ctivation.Science2010SepIdentifyanepithelialTcells-specificcostimulatorymolecule,JAML◆PetermannF,etal.Tcellsenhanceautoimmunitybyr

estrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-23-activatedrende

reffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionofconventionalTcellsintoFoxp3+Tregcell

sinvivo.TwonewpapersaboutTCellpublishedinthismonth❑NaïveTcells▪MatureTcellsthathavenotpreviouslyencounteredantigen;▪Preferentialmigrationt

osecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigen❑EffectorTcells▪ActivatedTcellscapableofper

formingthefunctionsrequiredtoeliminateforeignantigens▪Preferentialmigrationtositesofinfectionorinflammation▪S

hort-lived❑MemoryTcells▪Long-lived,functionallysilentcells;▪Mountrapidsecondaryimmuneresponsestothesameantigenexposu

re▪Heterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.NaiveTcellsEffecto

rTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPreferentiallytoinflamedtissuesPreferentiallytoinflamed

tissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffectorfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCe

llcyclingNoYes+/-SurfaceproteinexpressionHigh-affinityIL-2receptorLowHighLowPeripherallymphnodehomingreceptor(L-selectin,CD62L)High

LowLoworvariableAdhesionmolecules:integrins,CD44LowHighHighChemokinereceptor:CCR7HighLowVariableMajorCD45isof

orm(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytoplasmLarge;morecytoplasmSmall◆CentralmemoryTcell

s➢expressCCR7andL-selectin,andhometolymphnodes.➢limitedcapacitytoperformeffectorfunctionswhentheyencounterantigen➢gener

atemanyeffectorcellsuponantigenchallenge◆EffectormemoryTcells➢donotexpressCCR7orL-selectin,andhometoperipheraltissues,especial

lymucosa.➢produceeffectorcytokinesuponantigenicstimulation➢donotproliferatemuch.Basedontheirhomingpropertiesandeffectorfunctions.Subsetsofm

emoryTcellsCD4+CD8+CD4+➢Th1-Th2hypothesis1986CoffmanandMossman➢Th172006DiscoveryofCD4+ThcellsubsetsThesubsetsofCD4+Thcell

s▪Howtheyareinduced,▪Whatcytokinestheyproduce▪WhateffectormechanismstheyactivateTh0❑CytokinesStimulithatinfluencethepat

ternofThcelldifferentiation❑Highdosesofantigenwithoutadjuvants❑Differentsubsetsofdendriticcellsmayexist❑Thegeneticmak

eupofthehostPropertiesofCD4+Th1andTh2subsetsDifferentiationofTh1Subset❖Stimulatedbyintracellularmicrobesthat

infectoractivatemacrophagesorNKcellsListeria,mycobacteriaandLeishmania❖ImportantcytokinesfortheTh1differentia

tion❖Importanttranscriptionfactors(TF)fortheTh1differentiation▪IL-12▪IFN-▪IL-18▪typeIIFNs(inhuman)▪T-bet:masterregulator▪STAT4▪STAT1Themolecul

arbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT4IL-12STAT-4IF

N-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-DifferentiationofTh1subsetsDifferentia

tionofTh2Subset❖ImportantTFfortheTh2differentiation❖StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationw

ithlittleinflammationormacrophageactivationHelminthandallergens❖ImportantcytokinesfortheTh2differentiatio

n▪IL-4▪GATA-3:masterregulator▪STAT6ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,andtheTFGATA-3andS

TAT6Th2differentiationisdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-3GATA-3❑Enhancesexpressionoft

heTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatin

remodeling❑Enhancesitsownexpressionviaapositivefeedbackloop❑BlocksTh1differentiationAmasterregulatorofTh2differentiationDevelopmentofTh2

subsetsDevelopmentofTh1andTh2subsetsDifferentiationofTh17Subset❖Stimulatedbyzymosan,fungus,myobacteria❖ImportantcytokinesfortheTh17differentiatio

n❖Importanttranscriptionfactors(TF)fortheTh17differentiation▪IL-6▪TGF-▪IL-23▪IL-21▪ROR-t:masterregulator▪

ROR-▪STAT3▪AhRTh17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonT

h17generation.◆Veldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.Nature

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

e453,65–71(2008).◆Kimuraetal.ArylhydrocarbonreceptorregulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl

.Acad.Sci.USA105,9721–9726(2008).◆Veldhoen,etal.Naturalagonistsforarylhydrocarbonreceptorinculturemediumareessentialforoptimaldifferentia

tionofTh17Tcells.JExpMed,2009IMDMisbetterthan1640forTh17invitrodifferentiationThedifferentiationofTh17SubsetC

D4+CD25+RegulatoryTcells(Tregcells)➢AsubsetofCD4+CD25+TcellsexpressingFoxp3➢Naturallypresentinimmunesystem,constitute5-10%ofper

ipheralCD4+Tcells➢Suppressimmuneresponsesandmaintainself-tolerance◆Sakaguchietal.Immunologicself-toleranc

emaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tole

rancecausesvariousautoimmunediseases.JImmunol1995◆Horietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3

.Science2003◆Fontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003Landmarkp

apersaboutTregNaturalTregcells(nTreg)thymicderived,highlycontrolledbythymicmicroenvironmentInducedTregcells(iTreg)peripherallygeneratedSubsetso

fTregcells⚫TCR⚫Co-stimulation⚫Cytokine-mediatedsignalsJosefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcellsMechanismsofT

regcells-mediatedsuppressionDirectlysuppressresponderFoxp3-TcellsIndirectlyblocktheactivationofFoxp3-Tcellsbysuppressingt

hefunctionofAPCMechanismsofTregcells-mediatedsuppressionMajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,

2009MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,2009Subsets“inthe

making”FollicularhelperTcells(TFH)Th9Th22FollicularhelperTcells(TFH)➢PreferentiallyresidentinBcellfollicles➢ExpressCXCR5➢Producealargeamo

untofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansion➢DependontheBcl-6transcriptionfactor➢Essentialfort

hegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory◆Vogelzang,etal.GenerationofTfollicularhelpercellsisme

diatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immunity29,138–149(2008).◆Zaretsky

,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.206,991–999(2009).◆Kingetal.IL-4-producingCD4+Tcellsinr

eactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.J.Exp.Med.206,1001–1007(2009).◆Rainhardtetal.Cytokine-secretingfollicularT

cellsshapetheantibodyrepertoire.NatureImmunol.10,385–393(2009).ThreestudiesusedIL-4reportermiceandshowedthat,duringhelminthinfection,mostI

L-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programmedcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL

-6)andIL-21andlocalizedtotheBcellfollicles◆Johnstonetal.Bcl6andBlimp-1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldiffer

entiation.Science325,1006–1010(2009).Th9◆Veldhoen,M.etal.Transforminggrowthfactor-β‘reprograms’thediffere

ntiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,1341–1346(2008).Th2cellscanc

hangeintoanIL-9-producingTcelltype◆Nowak,E.C.etal.IL-9asamediatorofTh17-driveninflammatorydisease.J.Exp.Med.206,1653–1660(2

009).◆Elyaman,W.etal.IL-9inducesdifferentiationofTH17cellsandenhancesfunctionofFoxP3+naturalregulatoryTcells.Proc.Natl.Acad.Sci.USA106,12885–128

90(2009).◆Beriouetal.TGF-betainducesIL-9fromhumanTh17cells.JImmunol.2010◆Duhen,etal.Productionofinterleukin22butnotinterleukin17byasubs

etofhumanskin-homingmemoryTcells.NatureImmunol.10,857–863(2009).◆Trifari,etal.IdentificationofahumanhelperT

cellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17,TH1andTH2cells.NatureImmunol.10,864–871(20

09).Th22➢Inhuman,butnotmouse➢ExpressIL-22butnotIL-17orROR-t:➢Maypresentaskin-homingsubsetresponsibleforskininflammati

onsuchaspsoriasisApossiblehierarchyofstabilityTheflexibilityofTcellsubsets?Whataretheenvironmental(extrinsic)factorsthatallowforpl

asticity?Whatregulateslineagecommitmentversusflexibility?Whydoweneedsomanyfunctionalsubsets?Questions