T細(xì)胞亞群課件

T細(xì)胞亞群

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)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

Jensen,K.D.etal.

Thymicselectiondetermines

Tcelleffectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferonImmunity29,90–100(2008).

Epithelial

TcellandPeripheral

Tcell

CD27-IL-17+

TcellsandCD27+IFN-+

Tcells

SubsetsofTcells

Developmentalprogrammingof

Tcellsubsets.CuaDJ,etal.NaturereviewImmunology,2010

MartinBetal.IL-17-Producing

TcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironmentalSignals.

Immunity31,321–330(2009).

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(2009).

ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssuggestthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-17

Witherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimulatoryreceptorforepithelial

Tcellactivation.Science2010SepIdentifyanepithelial

Tcells-specificcostimulatorymolecule,JAMLPetermannF,etal.

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

Na?veTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigen

EffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.

CentralmemoryTcellsexpressCCR7andL-selectin,andhometolymphnodes.limitedcapacitytoperformeffectorfunctionswhentheyencounterantigengeneratemanyeffectorcellsuponantigenchallenge

EffectormemoryTcellsdonotexpressCCR7orL-selectin,andhometoperipheraltissues,duceeffectorcytokinesuponantigenicstimulationdonotproliferatemuch.Basedontheir

homingpropertiesandeffectorfunctions.SubsetsofmemoryTcells

CD4+CD8+CD4+Th1-Th2hypothesis1986CoffmanandMossmanTh172006DiscoveryofCD4+Thcellsubsets

CytokinesStimulithatinfluencethepatternofThcelldifferentiation

Highdosesofantigenwithoutadjuvants

DifferentsubsetsofdendriticcellsmayexistThegeneticmakeupofthehostPropertiesofCD4+Th1andTh2subsetsDifferentiationofTh1Subset

StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcells

Listeria,mycobacteriaandLeishmania

ImportantcytokinesfortheTh1differentiation

Importanttranscriptionfactors(TF)fortheTh1differentiation

IL-12

IFN-IL-18typeIIFNs(inhuman)

T-bet:masterregulatorSTAT4STAT1DifferentiationofTh1subsetsDifferentiationofTh2Subset

ImportantTFfortheTh2differentiation

StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcellstimulationwithlittleinflammationormacrophageactivation

Helminthandallergens

ImportantcytokinesfortheTh2differentiationIL-4GATA-3:masterregulatorSTAT6DevelopmentofTh2subsetsDevelopmentofTh1andTh2subsetsDifferentiationofTh17Subset

Stimulatedbyzymosan,fungus,myobacteria

ImportantcytokinesfortheTh17differentiation

Importanttranscriptionfactors(TF)fortheTh17differentiation

IL-6

TGF-IL-23

IL-21

ROR-t:masterregulator

ROR-

STAT3

AhRTh17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation.

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

IMDMisbetterthan1640forTh17invitrodifferentiationThedifferentiationofTh17SubsetCD4+CD25+RegulatoryTcells(Tregcells)

AsubsetofCD4+CD25+TcellsexpressingFoxp3

Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+TcellsSuppressimmuneresponsesandmaintainself-toleranceSakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpressingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995Horietal.ControlofregulatoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003Fontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTreg

NaturalTregcells(nTreg)

thymicderived,highlycontrolledbythymicmicroenvironmentInducedTregcells(iTreg)

peripherallygeneratedSubsetsofTregcells

TCRCo-stimulationCytokine-mediatedsignalsJosefowiczetal.Immunity,2009DifferentiationofthymicandinducedTregcellsMechanismsofTregcells-mediatedsuppression

DirectlysuppressresponderFoxp3-TcellsIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppression

MajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,2009MajormechanismsbywhichTregcellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,2009Subsets“inthemaking”FollicularhelperTcells(TFH)Th9Th22FollicularhelperTcells(TFH)

PreferentiallyresidentinBcellfolliclesExpressCXCR5ProducealargeamountofIL-21,whichactsinanautocrine

mannertogetherwithIL-6promotetheirdifferentiationandexpansionDependontheBcl-6transcriptionfactorEssentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory

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).Th9

Veldhoen,M.etal.Transforminggrowthfactor-β‘reprograms’thedifferentiationofThelper2cellsandpromotesaninterleukin9-producingsubset.Nat.Immunol.9,1341–1346(2008).Th2cellscanchangeintoanIL-9-producingTcelltypeNowak,E.C.etal.IL