Th2细胞的分化过程

Chapter10–DifferentiationandFunctionsofCD4+EffectorTCells234cellsareincompletelydefinedandmayincludeIL-25,IL-33andthymicstromallymphopoietinproducedbydamagedepithelialandothercells.IL-4producedbymastcellsandbyTh2cellsthemselvespromotesfurtherTh2differentiation.IL-4stimulatesTh2developmentbyactivatingthetranscriptionfactorSTAT6,which,togetherwithTcellreceptor(TCR)signals,inducesexpressionofGATA-3(seemicrobesafterphagosomesfusewithlysosomes(seeFig.4.12).Thesetoxicsubstancesmayalsobereleasedintoadjacenttissues,wheretheykillextracellularmicrobesandmaycausedamagetonormaltissues.Inheritedimmunodeficiencies,aswellasgeneknockoutmice,haveestablishedthecriticalimportanceofCD40L-CD40interactions,inadditiontoIFN-γ,incell-mediatedimmunityagainstintracellularpathogens.HumanswithinheritedmutationsinCD40L(X-linkedhyper-IgMsyndrome)andmiceinwhichthegeneforCD40orCD40Lisknockedoutarehighlysuscep-tibletoinfectionswithmicrobes,includingthefungusPneumocystisjiroveci(seeChapter21),whichrequireTcell–dependentmacrophageactivationtobeeradicated.ThesepatientsandknockoutmicealsohavedefectsinhelperTcell–dependentantibodyproduction,becauseofthecriticalroleoftheCD40L-CD40interactioninBcellactivation(seeChapter12).RarepatientsmakeautoantibodiesagainsttheirownIFN-γandaresusceptibletodisseminatedmycobacterialinfections.MacrophagesactivatedbyTh1cellsareinvolvedinseveralotherreactionsofhostdefense(seeFig.10.7).Theystimulateinflammationthroughthesecretionofcytokines,mainlyTNF,IL-1,andchemokines,andshort-livedlipidmediators,suchasprostaglandins,leukotri-enes,andplatelet-activatingfactor.Thecollectiveactionofthesemacrophage-derivedmediatorsofinflammationistorecruitmoreleukocytes,whichenhancesthehost’sabilitytodestroyinfectiousorganisms.Activatedmac-rophagesmayamplifycell-mediatedimmuneresponsesbybecomingmoreefficientAPCsbecauseofincreasedlevelsofmoleculesinvolvedinantigenprocessingandincreasedsurfaceexpressionofclassIIMHCmoleculesandcostimulators,andbyproducingcytokines(suchasIL-12)thatstimulateTlymphocytedifferentiationintoeffectorcells.SometissueinjurymaynormallyaccompanyTh1cell–mediatedimmunereactionstomicrobesbecausethemicrobicidalproductsreleasedbyactivatedmacrophagesandneutrophilsarecapableofinjuringnormaltissueanddonotdiscriminatebetweenmicrobesandhosttissue.However,thistissueinjuryisusuallylimitedinextentandduration,anditresolvesastheinfectioniscleared.THETh2SUBSETTheTh2subsetisthemediatorofphagocyte-independentdefense,inwhicheosinophilsandmastcellsplaycentralroles.Thesereactionsareimportantfortheeradicationofhelminthicinfectionsandperhapsalsoforelimina-tionofothermicrobesinmucosaltissues.Theyarealsocentraltothedevelopmentofallergicdiseases(seeChapter20).DevelopmentofTh2CellsTh2differentiationoccursinresponsetohelminthsandallergensandisenhancedbythecytokineIL-4(Fig.10.8).ThecytokinesthatinitiatethedevelopmentofTh2DendriticcellHelminthsorproteinantigensIL-25,IL-33,TSLPEpitheliumNaiveTcellMastcellsTh2cellsIL-4IL-5IL-13?STAT6GATA-3IL-4IL-4IL-4?IL-4AmplificationFIGURE10.8DevelopmentofTh2cells.DendriticcellsmayrespondtocytokinesproducedinepitheliabybecomingTh2inducers,bymechanismsthatarenotwelldefined.IL-4producedbyactivatedTcellsthemselvesorbymastcellsandeosinophils,especiallyinresponsetohelminths,activatesthetranscriptionfactorsGATA-3andSTAT6,whichstimulatethedifferentiationofnaiveCD4+TcellstotheTh2subset.IL-4producedbytheTh2cellsamplifiesthisresponseandinhibitsthedevelopmentofTh1andTh17cells.