Th17细胞的分化过程

Chapter10–DifferentiationandFunctionsofCD4+EffectorTCells238strongTh1andTh2responsestendtosuppressTh17development.ThedevelopmentofTh17cellsisdependentonthetranscriptionfactorsRORγtandSTAT3(seeFig.10.11).TGF-βandtheinflammatorycytokines,mainlyIL-6andIL-1,workcooperativelytoinducetheproductionofRORγt,atranscriptionfactorthatisamemberoftheretinoicacidreceptorfamily.RORγtisaTcell–restrictedproteinencodedbytheRORCgene,sosometimestheproteinmaybecalledRORc.Inflammatorycyto-kines,notablyIL-6,activatethetranscriptionfactorSTAT3,whichfunctionswithRORγttodrivetheTh17response.Th17cellsappeartobeabundantinmucosaltissues,particularlyofthegastrointestinaltract,suggestingthatthetissueenvironmentinfluencesthegenerationofthissubset,perhapsbyprovidinghighlocalconcentrationsofTGF-βandinflammatorycytokines.ThisobservationalsosuggeststhatTh17cellsmaybeespeciallyimportantincombatingintestinalinfectionsandinthedevelopmentofpathologicintestinalinflammation.ThedevelopmentofTh17cellsinthegastrointestinaltractisdependentonthelocalmicrobialpopulation;inmice,somecommensalbacteriarelatedtoClostridiumspeciesareparticularlypotentinducersofTh17cells.FunctionsofTh17CellsTh17cellscombatmicrobesbyrecruitingleukocytes,mainlyneutrophils,tositesofinfection(Fig.10.12).Becauseneutrophilsareamajordefensemechanismagainstmanycommonbacteriaandfungi,Th17cellsplayanimportantroleindefenseagainsttheseinfections.Mostoftheinflammatoryactionsofthesecellsaremedi-atedbyIL-17,butothercytokinesproducedbythissubsetmayalsocontribute.Interleukin-17IL-17isanunusualcytokinebecauseneitheritnoritsreceptorishomologoustoanyotherknowncytokine-receptorpair.TheIL-17familyincludessixstructurallyrelatedproteins,ofwhichIL-17AandIL-17Farethemostsimilar,andtheimmunologicfunctionsofthiscyto-kinefamilyaremediatedprimarilybyIL-17A.IL-17AisproducedbyTh17cellsaswellasinnatelymphoidcellsandsomeγδandCD8+Tcells.IL-17receptorsaremultimericandexpressedonawiderangeofcells(seeChapter7).IL-17isanimportantlinkbetweenTcell–mediatedadaptiveimmunityandtheacuteinflammatoryresponse,whichwediscussedinChapter4asoneofthemajorreactionsofinnateimmunity.Thetermimmuneinflam-mationissometimesusedtoindicatethestronginflam-matoryreactionthatmayaccompanyTcellresponses;inmanycases,thesereactionsaremoresevereandpro-longedthanwhatisseenininnateimmunity,whenTcellsarenotinvolved.IL-17hasseveralimportantfunctionsinhostdefense.•IL-17inducesneutrophil-richinflammation.Itstimulatestheproductionofchemokinesandothercytokinesthatrecruitneutrophilsand,toalesserIL-1stimulatetheearlystepsinTh17differentiation,IL-23maybemoreimportantfortheproliferationandmaintenanceofdifferentiatedTh17cells.AsurprisingaspectofTh17differentiationisthatTGF-β,whichisproducedbymanycelltypesandisanantiinflammatorycytokine(seeChapter15),promotesthedevelopmentofproinflammatoryTh17cellswhenothermediatorsofinflammation,suchasIL-6orIL-1,arepresent.Th17differentiationisinhibitedbyIFN-γandIL-4;therefore,DendriticcellBacteria,fungiNaiveTcellNumeroussourcesIL-22IL-17TGF-βTGF-βIL-6IL-6IL-1IL-23IL-21RORγtTh17cellsSTAT3AmplificationFIGURE10.11DevelopmentofTh17cells.IL-1andIL-6producedbyAPCsandtransforminggrowthfactor-β(TGF-β)producedbyvariouscellsactivatethetranscriptionfactorsRORγtandSTAT3,whichstimulatethedifferentiationofnaiveCD4+TcellstotheTh17subset.IL-23,whichisalsoproducedbyAPCs,especiallyinresponsetofungi,stabilizestheTh17cells.TGF-βmaypromoteTh17responsesindirectlybysuppressingTh1andTh2cells,bothofwhichinhibitTh17differentiation(notshown).IL-21producedbytheTh17cellsamplifiesthisresponse.