GuidanceFactorsOrchestratingRegulatoryTCellPositioninginTissuesduringDevelopment,Homeostasis,andResponseThorstenR.MempelandFrancescoMarangoniTheCenterforImmunologyandInflammatoryDiseasesatMassachusettsGeneralHospitalandHarvardMedicalSchool,Boston,MASummaryOvertheirlifetime,regulatoryTcells(Treg)recalibratetheirexpressionoftraffickingreceptorsmultipletimesastheyprogressthroughdevelopment,respondtoimmunechallenges,oradapttotherequirementsoffunctioninginvariousnon-lymphoidtissue(NLT)environments.Thesetraffickingreceptors,whichincludechemokinereceptors(CKRs)andotherG-proteincoupledreceptors(GPCRs),integrins,aswellasselectinsandtheirligands,enableTregnotonlytoenterappropriatetissuesfromthebloodstreamviapost-capillaryvenules,butalsotonavigatethesetissuestolocallyexecutetheirimmune-regulatoryfunctions,andfinallytoseekouttherightantigen-presentingcellsandinteractwiththese,inpartinordertoreceivethesignalsthatsustaintheirsurvival,proliferation,andfunctionalactivity,inpartinordertoexecutetheirimmuno-regulatoryfunctionbyalteringAPCfunction.Here,wewillreviewourcurrentknowledgeofwhenandinwhatwaysTregaltertheirtraffickingproperties.Wewillfocusonthechemokinesystemandtrytoidentifyspecialized,non-redundantrolesofindividualreceptorsaswellassimilaritiesanddifferencestotheconventionalTcellcompartment.KeywordsTregulatorycells(Treg);migration;trafficking;chemokines;tissueenvironment;toleranceIntroductionCD4+Foxp3+TregareαTcellsspecializedinthemaintenanceofimmunehomeostasisandtheregulationofimmuneresponses.Theirmajority(~80%)developinthethymustoproducepreferentiallyself-reactivethymicTreg(tTreg),butsomealsoemergethroughextra-thymicconversionofconventionalCD4+cellstogenerateperipheralTreg(pTreg)thatarereactivewithcommensal,food,andotherenvironmentalantigens.Ineachcase,thetranscriptionfactorFoxp3orchestratesgeneexpressionprogramsthatrestraintheirproinflammatoryeffectorfunctionsandinsteadendowthemwithamultitudeofimmune-regulatoryfunctions.Asforallcellsoftheimmunesystem,Treghavetopositiont...
