Signal transduction and Th17 cell differentiation

SignaltransductionandTh17celldifferentiationJohnJ.O’Sheaa,ScottM.Steward-Tharpa,b,*,ArianLaurencea,WendyT.Watforda,LaiWeia,AdewoleS.Adamsona,c,andSamuelFana,daMolecularImmunologyandInflammationBranch,NationalInstitutesofArthritis,andMusculoskeletalandSkinDiseases,NationalInstitutesofHealth,Bethesda,MD20892bHowardHughesMedicalInstitute-NationalInstitutesofHealthResearchScholarsProgram,Bethesda,MD20814cHarvard-MassachusettsInstituteofTechnologyDivisionofHealthSciencesandTechnology,Boston,MA02115dDepartmentofBiology,BradleyUniversity,Peoria,IL61625AbstractTheparadigmofeffectorThelpercelldifferentiationintoeitherTh1orTh2lineageshasbeennotablyshakenbythediscoveryofathirdlineageofcellsthatselectivelyproduceinterleukin(IL)-17.Characterizationofthisnewsubset,referredtoasTh17,hasprovidedexcitingnewinsightsintoimmunoregulation,hostdefenseandthepathogenesisofautoimmunediseases.Additionally,thediscoveryofthisTcellsubsethasofferedafreshlookatsuchconceptsaslineagecommitmentandterminaldifferentiation.Thetranscriptionalregulatoryeventsandepigeneticmodificationsthatcontroltheseprocessesarediverseandcomplex,anddespitetherapidpaceatwhichdatacontinuestoaccumulate,manyquestionsremaintobeanswered.Herewereviewourcurrentunderstandingofthesignalingpathways,molecularinteractionsandtranscriptionaleventsthatleadtoTh17differentiationandeffectorfunction,aswellastheepigeneticmodificationsthataccompanythem.KeywordsTh17;IL-17;Signaltransduction;Transcriptionfactor;Lymphocytedifferentiation;Cytokines;ChromatinIntroductionSuccessfulhostdefensereliesoncommunicationbetweencellsoftheinnateandadaptiveimmunesystem.TheseminalstudiesinitiatedbyCoffmanandMossmanandexpandedbymanyothers,providedthefirstcluesofhowhelperTcellsorchestrateproperinnateandadaptiveresponsestomicrobialpathogens[1–3].ThesestudiesalsoprovidedconsiderableinsightintoourunderstandingofTcellactivationandtheselectiveregulationofgeneexpression,providingrobustmodelsforunderstandingmechanismsofgeneregulationandTcellfatedetermination[2,4,5][6].Despiteitsutility,asimple,staticTh1/Th2viewofTcelldifferentiationimpliesratherinflexibleresponses,butrecentdiscoverieshaveemphasizedthatTcellsareanythingbutstaticintheirresponses.*Correspondingauthor.Telephone:[phone].Fax:[e-mail]:10CenterDrRM13C103Bethesda,MD,20892-1930.NIHPublicAccessAuthorManuscriptMicrobesInfect.Authormanuscript;availableinPMC2009September29.Publishedinfinaleditedformas:MicrobesInfect.2009April;11(5):599–611.doi:10.1016/j.micinf.2009.04.007.NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscriptWenowappreciatethatIL-17-producinghelperTcellsorTh17cellsrepresentanothersubsetofCD4+Tcells.Thesecellshavecriticalrolesinhostdefenseagainstextracellularbacteriaandalsoplaypivotalrolesinthepathogenesisofautoimmunedisease.Th17cellsproducearangeofcytokinesincludingTNF,IL-17A,IL-17F,IL-21andIL-22,butasimplisticviewofthesecellsasmerelyanother“lineage”ofTcellsunravelssomewhatwhenoneconsidersanumberofpoints.First,itisapparentinvitroandinvivothatsomeTcellscanproducebothIFN-γandIL-17;exactlywherethesecellsfitinthespectrumofTh17andTh1cellsisunclear.Inhumans,IL-17/IFN-γdoubleproducersandIL-17singleproducerscanbedistinguishedbytheirchemokinereceptorexpression[7].Second,althoughIL-21andIL-22areproducedbyTh17cells,theycanalsobeproducedintheabsenceofIL-17[8–10].Third,wenowrecognizethatTh17cells,aswellasotherTcellsubsetsproduceIL-10;asaresult,notallTh17cellsare“pathogenic”[11].Finally,thereisevidencethatanothercriticalsubsetofCD4+Tcells,regulatoryT(Treg)cells,isrelatedtoTh17cells[12].TregcellsareCD4+CD25+cellsfoundinthethymusandintheperiphery,whichexpresstheforkheadboxproteintranscriptionfactor,Foxp3.WenowknowthatsomeofthefactorsthatcontributetothedifferentiationofTregsalsodriveTh17differentiation,andthereisevidenceindicatingthatTregcellscanbecomepathogenicTh17cells.Additionally,therearedataindicatingthatTh17cellscanexpressFoxp3andthattherespectiveTh17andTreglineage“masterregulators”interact.Inthisreview,wewilldiscussthereceptorsandsignalingpathwaysthatpromotethedifferentiationofTh17cells,bearinginmindthattheconceptofaTh17cellmaybeamovingtarget.Th17cellsarecapableofproducingarangeofcytokinesandmaynotalwaysconstituteastable“lineage”.Consequently,understandingtheregulationofIL-17isnotsynonymouswith“lineagecommitment”orterminaldifferentiationofTh17cells–ifindeed,thisconceptisappropriate.TcellreceptorsignalingForanyTcell,thefirststepsintheactivationprocessoccurasconsequencesofantigenbindingtotheTcellreceptor(TCR).FornaïveCD4+Tcells,TCRsignalstrengthisawell-knownfactorinfluencingTh1versusTh2differentiation[13].StrongTCRsignalingupregulatestheTh1-associatedtranscriptionfactorT-bet,whichisamajorregulatorofIFN-γproduction,whereasweaksignalsfavorIL-4production.TCR-dependentsignalsalsoplayanimportantroleinTh17differentiationandIL-17production,asexemplifiedbythefindingsthatinvariantNKTcells,gamma-deltaTcells,andmemoryCD4+TcellsallproduceIL-17inresponsetoTCRoccupancy[14–16].However,theimportanceof“stro