【文档说明】T细胞亚群医学知识课件.ppt，共(52)页，4.589 MB，由小橙橙上传

转载请保留链接：https://www.ichengzhen.cn/view-245912.html

以下为本文档部分文字说明：

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

）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TCellsubsetsClass

FunctionsAntigenreceptorandspecificitySelectedmarkersPercentoftotallymphocytes(human)αβTlymphocytesBloodLymphnode

SpleenCD4+helperTlymphocytesBcelldifferentiation(humoralimmunity)Macrophageactivation(cell-mediatedimmunity)αβheterodimersDiversespecificitie

sforpeptide-classIIMHCcomplexesCD3+,CD4+,CD8-50-60*50-6050-60CD8+cytotoxicTlymphocytesKillingofcellinfectedwithmicrobes,killingoftumorcell

sαβheterodimersDiversespecificitiesforpeptide-classIMHCcomplexesCD3+,CD4-,CD8+20-2515-2010-15RegulatoryTcellsSuppressfunction

ofotherTcells(regulationofimmuneresponses,maintenanceofself-tolerance)αβheterodimersCD3+,CD4+,CD25+(Mostcommon,butotherphenotypesasw

ell)Rare1010γδTlymphocytesHelperandcytotoxicfunctions(innateimmunity)γδheterodimersLimitedspecificitiesforpeptideandnonpept

ideantigensCD3+,CD4,andCD8variableTcells➢expressalimitednumberofTCRs➢abundantinepithelialtissuesofcertainspec

ies:inthesmallbowelmucosaandintheskinofmouse.Intheskin,knownasadendriticepidermalTcell(DETC)➢donotrecognizeMHC-associatedpept

ideantigensandarenotMHCrestricted.➢maybindtoconservedligandswhoseexpressionistriggeredbycellinjuryorstress,suc

hasmicrobialheatshockproteins.➢mayrepresentanimportantbridgebetweeninnateandadaptiveimmunity,functioningasl

ymphocytesthatenhancethefirstlineofdefenseagainstarangeofpathogens.Jensen,K.D.etal.ThymicselectiondeterminesTcell

effectorfate:antigen-naivecellsmakeinterleukin-17andantigen-experiencedcellsmakeinterferonImmunity29,90–100(2008).Epi

thelialTcellandPeripheralTcellCD27-IL-17+TcellsandCD27+IFN-+TcellsSubsetsofTcellsDevelopmentalprogrammingofTcellsubsets.CuaDJ,etal.Natu

rereviewImmunology,2010◆MartinBetal.IL-17-ProducingTcellsSelectivelyExpandinResponsetoPathogenProductsandEnvironm

entalSignals.Immunity31,321–330(2009).TheyshowthatT-17cellsadditionallyexpressIL-23R,andtheinnatereceptorsTLR2anddectin-1,whichrecog

nizearchetypicalandfungalconstituents.TheseT-17cellsusethesereceptorstorapidlyproduceIL-17inresponsetobystandercell-derive

dIL-23andtobacteriaandfungiwithoutconcomitantTCRstimulation.OneoftherolesofT-17-derivedmaybeindirectordirectamplificationofIL-17productio

ninTh17cells.◆Sutton,C.E.etal.Interleukin-1andIL-23induceinnateIL-17productionfromTcells,amplifyingTh17responsesandautoimmunity.

Immunity31,331–341(2009).ThisreportshowsthatTcellshaveanearlyroleinpromotingCNSinflammation.Theauthorssugg

estthatinnatecell-producedIL-17directlyenhancesdevelopmentofMOG-specificTh17cells.AmajorinnatesourceofIL-17InnateActivationofIL-17

-ProductionbyaSpecializedTCellSubsetKapsenbergML.Immunity,2009◆Witherden,etal.ThejunctionaladhesionmoleculeJAMLisacostimul

atoryreceptorforepithelialTcellactivation.Science2010SepIdentifyanepithelialTcells-specificcostimulatorymolecule,JA

ML◆PetermannF,etal.TcellsenhanceautoimmunitybyrestrainingregulatoryTcellsresponsesviaanIL-23-dependengmechanism.Immunity,2010SepIL-2

3-activatedrendereffectorTcellsrefractorytothesuppressiveactivityofTregcellsandalsopreventedtheconversionof

conventionalTcellsintoFoxp3+Tregcellsinvivo.TwonewpapersaboutTCellpublishedinthismonth❑NaïveTcells▪Mature

Tcellsthathavenotpreviouslyencounteredantigen;▪Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),where

theyrecognizeantigen❑EffectorTcells▪ActivatedTcellscapableofperformingthefunctionsrequiredtoeliminatefore

ignantigens▪Preferentialmigrationtositesofinfectionorinflammation▪Short-lived❑MemoryTcells▪Long-lived,functionallysilentcells;▪M

ountrapidsecondaryimmuneresponsestothesameantigenexposure▪Heterogenous(centralandeffector)Basedonthehistoryofantigene

ncounterandthestageofTcellactivation.NaiveTcellsEffectorTcellsMemoryTcellsMigrationPreferentiallytoperipherallymphoidtissuesPrefere

ntiallytoinflamedtissuesPreferentiallytoinflamedtissues,mucosaltissuesFrequencyofcellsresponsivetoparticularantigenVerylowHighLowEffec

torfunctionsNoneCytokinesecretion;cytotoxicactivityNoneCellcyclingNoYes+/-SurfaceproteinexpressionHigh-affinityIL-2receptorLowHighLowPeripherallym

phnodehomingreceptor(L-selectin,CD62L)HighLowLoworvariableAdhesionmolecules:integrins,CD44LowHighHig

hChemokinereceptor:CCR7HighLowVariableMajorCD45isoform(humansonly)CD45RACD45ROCD45RO;variableMorphologySmall;scantcytopla

smLarge;morecytoplasmSmall◆CentralmemoryTcells➢expressCCR7andL-selectin,andhometolymphnodes.➢limitedcapacitytoperformeffectorfunctionswhentheyen

counterantigen➢generatemanyeffectorcellsuponantigenchallenge◆EffectormemoryTcells➢donotexpressCCR7orL-selectin,andhometope

ripheraltissues,especiallymucosa.➢produceeffectorcytokinesuponantigenicstimulation➢donotproliferatemuch.Basedont

heirhomingpropertiesandeffectorfunctions.SubsetsofmemoryTcellsCD4+CD8+CD4+➢Th1-Th2hypothesis1986CoffmanandMossman➢Th172

006DiscoveryofCD4+ThcellsubsetsThesubsetsofCD4+Thcells▪Howtheyareinduced,▪Whatcytokinestheyproduce▪WhateffectormechanismstheyactivateTh0❑Cy

tokinesStimulithatinfluencethepatternofThcelldifferentiation❑Highdosesofantigenwithoutadjuvants❑Differe

ntsubsetsofdendriticcellsmayexist❑ThegeneticmakeupofthehostPropertiesofCD4+Th1andTh2subsetsDifferentiationofTh1Subset

❖StimulatedbyintracellularmicrobesthatinfectoractivatemacrophagesorNKcellsListeria,mycobacteriaandLeishmania❖ImportantcytokinesfortheTh1d

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

TAT1ThemolecularbasisofTh1differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokinesIFN-andIL-12,andtheTFT-bet,STAT1,andSTAT

4IL-12STAT-4IFN-STAT-1AgrecognitionbyTCRT-betApositiveamplificationloopbetweenT-betandIFN-Differentiationof

Th1subsetsDifferentiationofTh2Subset❖ImportantTFfortheTh2differentiation❖StimulatedbymicrobesandantigensthatcausepersistentorrepeatedTcell

stimulationwithlittleinflammationormacrophageactivationHelminthandallergens❖ImportantcytokinesfortheTh2differentiation

▪IL-4▪GATA-3:masterregulator▪STAT6ThemolecularbasisofTh2differentiationTheinterplayofsignalsfromtheTcellreceptor,thecytokineIL-4,a

ndtheTFGATA-3andSTAT6Th2differentiationisdependentonIL-4IL-4STAT-6AgrecognitionbyTCRGATA-3GATA-3❑Enhancesexpression

oftheTh2cytokinegenesIL-4,IL-5,andIL-13by1)directlyinteractingwiththepromotersofthesegenes2)causingchromatinremodeling

❑Enhancesitsownexpressionviaapositivefeedbackloop❑BlocksTh1differentiationAmasterregulatorofTh2differentiationDevelopmentofTh2subsetsDevelopmentofTh

1andTh2subsetsDifferentiationofTh17Subset❖Stimulatedbyzymosan,fungus,myobacteria❖ImportantcytokinesfortheTh17differentia

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

lator▪ROR-▪STAT3▪AhRTh17andAhRTheroleofAhRinTh17developmentandeffectorfunctionrevealedanenvironmentaleffectonTh17generation

.◆Veldhoenetal.ThearylhydrocarbonreceptorlinksTH17-cell-mediatedautoimmunitytoenvironmentaltoxins.Nature453,106–109(2008).◆Quintanaetal.Con

trolofTregandTH17celldifferentiationbythearylhydrocarbonreceptor.Nature453,65–71(2008).◆Kimuraetal.Arylhydrocarbonreceptor

regulatesStat1activationandparticipatesinthedevelopmentofTh17cells.Proc.Natl.Acad.Sci.USA105,9721–9726(2008).◆Veldhoen,etal.Naturalagonistsforaryl

hydrocarbonreceptorinculturemediumareessentialforoptimaldifferentiationofTh17Tcells.JExpMed,2009IMDMis

betterthan1640forTh17invitrodifferentiationThedifferentiationofTh17SubsetCD4+CD25+RegulatoryTcells(Tregc

ells)➢AsubsetofCD4+CD25+TcellsexpressingFoxp3➢Naturallypresentinimmunesystem,constitute5-10%ofperipheralCD4+Tcells➢Suppressimmuneresp

onsesandmaintainself-tolerance◆Sakaguchietal.Immunologicself-tolerancemaintainedbyactivatedTcellsexpre

ssingIL-2receptoralpha-chains(CD25).Breakdownofasinglemechanismofself-tolerancecausesvariousautoimmunediseases.JImmunol1995◆Horietal.Controlofregul

atoryTcelldevelopmentbythetranscriptionfactorFoxp3.Science2003◆Fontenotetal.Foxp3programsthedevelopmentandfunctionofCD4+CD25+

regulatoryTcells.NatureImmunol2003LandmarkpapersaboutTregNaturalTregcells(nTreg)thymicderived,highlycontrolledbythymicmicroenvironmentInduced

Tregcells(iTreg)peripherallygeneratedSubsetsofTregcells⚫TCR⚫Co-stimulation⚫Cytokine-mediatedsignalsJosefow

iczetal.Immunity,2009DifferentiationofthymicandinducedTregcellsMechanismsofTregcells-mediatedsuppressionD

irectlysuppressresponderFoxp3-TcellsIndirectlyblocktheactivationofFoxp3-TcellsbysuppressingthefunctionofAPCMechanismsofTregcells-mediatedsuppres

sionMajormechanismsbywhichTregcellscandirectlysuppressresponderFoxp3-TcellsShevach.Immunity,2009MajormechanismsbywhichTreg

cellscansuppressthefunctionofAPCandindirectlyblockoftheactivationofFoxp3-TcellsShevach.Immunity,2009Subsets“in

themaking”FollicularhelperTcells(TFH)Th9Th22FollicularhelperTcells(TFH)➢PreferentiallyresidentinBcellfollicles➢Expres

sCXCR5➢ProducealargeamountofIL-21,whichactsinanautocrinemannertogetherwithIL-6promotetheirdifferentiationandexpansion➢Dependo

ntheBcl-6transcriptionfactor➢Essentialforthegenerationofhigh-affinityisotypeswitchedantibodiesandBcellmemory◆Vogelzang,etal.Gener

ationofTfollicularhelpercellsismediatedbyinterleukin-21butindependentofThelper1,2,or17celllineages.Immu

nity29,138–149(2008).◆Zaretsky,etal.TfollicularhelpercellsdifferentiatefromTh2cellsinresponsetohelminthantigens.J.Exp.Med.206,991–999(2009).◆Kin

getal.IL-4-producingCD4+TcellsinreactivelymphnodesduringhelminthinfectionareTfollicularhelpercells.J.Exp.Med.206,1001

–1007(2009).◆Rainhardtetal.Cytokine-secretingfollicularTcellsshapetheantibodyrepertoire.NatureImmunol.10,385–393(2009).ThreestudiesusedI

L-4reportermiceandshowedthat,duringhelminthinfection,mostIL-4-expressingCD4+TcellsalsoexpressedtheTFHcellmarkersCXCR5,programm

edcelldeathprotein1(PD-1),inducibleTcellco-stimulator(ICOS),Bcelllymphoma6(BCL-6)andIL-21andlocalizedtotheBcell

follicles◆Johnstonetal.Bcl6andBlimp-1arereciprocalandantagonisticregulatorsofTfollicularhelpercelldifferentiat

ion.Science325,1006–1010(2009).Th9◆Veldhoen,M.etal.Transforminggrowthfactor-β‘reprograms’thedifferentiationofThelper2cellsandpromotes

aninterleukin9-producingsubset.Nat.Immunol.9,1341–1346(2008).Th2cellscanchangeintoanIL-9-producingTcelltype◆Nowak,E.C.etal.IL-9asamed

iatorofTh17-driveninflammatorydisease.J.Exp.Med.206,1653–1660(2009).◆Elyaman,W.etal.IL-9inducesdifferentiationofTH17cell

sandenhancesfunctionofFoxP3+naturalregulatoryTcells.Proc.Natl.Acad.Sci.USA106,12885–12890(2009).◆Beriouetal.TGF-betainducesIL-9fromhumanTh

17cells.JImmunol.2010◆Duhen,etal.Productionofinterleukin22butnotinterleukin17byasubsetofhumanskin-homingmemoryTcells.NatureImmunol.

10,857–863(2009).◆Trifari,etal.IdentificationofahumanhelperTcellpopulationthathasabundantproductionofinterleukin22andisdistinctfromTH-17,TH1andT

H2cells.NatureImmunol.10,864–871(2009).Th22➢Inhuman,butnotmouse➢ExpressIL-22butnotIL-17orROR-t:➢Maypresentaskin-ho

mingsubsetresponsibleforskininflammationsuchaspsoriasisApossiblehierarchyofstabilityTheflexibilityofTcellsubsets?Whataretheenvironmental(extrinsi

c)factorsthatallowforplasticity?Whatregulateslineagecommitmentversusflexibility?Whydoweneedsomanyfunctionalsubsets?Questions