retinoichdsky

COMMENTOpenAccessFOXP3andGARP(LRRC32):themasteranditsminionMichaelProbst-Kepper1*,JanBuer2AbstractThetranscriptionfactorFOXP3isessentialforthedevelopmentandfunctionofCD4+CD25hiFOXP3+regulatoryT(Treg)cells,butalsoexpressedinactivatedhumanhelperTcellswithoutacquisitionofaregulatoryphenotype.
Thiscommentfocusesonglycoprotein-Arepetitionspredominant(GARPorLRRC32)recentlyidentifiedasspecificmar-kerofactivatedhumanTregcells,whichmayprovidethemissinglinktowardabettermoleculardefinitionoftheregulatoryphenotype.
Reviewers:DrJimDiDanto,DrBeneditaRochaandDrWernerSolbach.
IntroductionProposedroleofFOXP3inself-toleranceThemaintenanceofself-toleranceinvolvescentralandperipheralmechanisms,buttheprocessofthymicnega-tiveselectionisimperfect.
Self-reactingclonesthatescapecentraltolerancearekeptincheckbyavarietyofperipheraltolerancemechanisms,inwhichthedomi-nanttoleranceexertedbyCD4+CD25+regulatoryT(Treg)cellsplaysanimportantrole.
ThedevelopmentandfunctionofTregcellscruciallydependsonthefork-head/wingedhelixtranscriptionfactorFOXP3.
ThisdependenceiscompellinglyillustratedbythefactthatlossoffunctionofFOXP3leadstothedevelopmentofthefatalautoimmunelymphoproliferativedisorderIPEX(immunodysregulation,polyendocrinopathy,andentero-pathy,X-linked)syndrome[1,2].
Similarly,lossoffunc-tionofFoxP3inmice,eithernatural(scurfy)orrecombinant,resultsinananalogousimmunepathologyduetoalackofTregcells[3-5].
ThedominantroleofFOXP3isfurthercorroboratedbythefactthatthegainoffunctioninducedbyectopicexpressioninconven-tionalCD4+CD25-helperT(Th)cellsleadstotheacqui-sitionofsuppressorfunctionandtheinductionofapartialregulatoryphenotypeinmiceandhumans[3,6-8].
DespiteadvancesinourunderstandingofTreg-celllineagecommitmentandfunction,gainedmainlybythestudyofFoxP3knock-out/knock-inmice[4,5,9-11],thedominantroleofFOXP3inthehumansystemanditssuitabilityasabonafidemarkerofhumanTregcellshavebeenquestioned[8,12-14].
WhyshouldTregcellsneedmorethanFOXP3ThereasoningthatmorethanFOXP3isnecessaryforfullyexplainingtheregulatoryphenotypeinhumansissupportedbyseveralobservations.
First,T-cellreceptor(TCR)stimulationofCD4+CD25-FOXP3-TcellsleadstotheinductionofFOXP3withoutinterferingwiththeexpressionofeffectorcytokinessuchasinterleukin-2andinterferon-g[15-17].
Second,theexpressionofFOXP3byconventionalCD4+CD25-ThcellsandevenbyThlinesandclonesdoesnotnecessarilyindicatetheacquisitionofsuppressorfunction[8,12,17-19].
Third,andmorespecifically,ithasrecentlybeenfoundthatdemethylationofaconservedFOXP3intronicregionmaybeabettermarkerforsuppressorfunctionthanthedifferentialexpressionofFOXP3atthemRNAorpro-teinlevelinTregandThcellclones[20].
Fourth,ectopicexpressionofFOXP3inhumanThcellsdoesnotleadtotheestablishmentofastableregulatoryphenotype[8,12,21].
Finally,althoughtheenhancementofFOXP3expressionbytransforminggrowthfactor-b1(TGF-b1)inactivatedhumanCD4+CD25-Thcellsgeneratesso-calledinducedTreg(iTreg)cells,thisphenotypeisrapidlylost[19,21,22].
Altogether,theseobservationssuggestthatmorethanFOXP3isnecessaryforfullyexplainingtheregulatoryphenotype.
Aplausibleexplanationforthequalitativeandquanti-tativedifferencesintheexpressionofFOXP3inhumanThandTregcells,withtheirmutuallyexclusiveeffector*Correspondence:m.
probst-kepper@klinikum-braunschweig.
de1InstituteforMicrobiology,ImmunologyandHygiene,StdtischesKlinikumBraunschweiggGmbH,Braunschweig,GermanyProbst-KepperandBuerBiologyDirect2010,5:8http://www.
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com/content/5/1/82010Probst-KepperandBuer;licenseeBioMedCentralLtd.
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0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
andregulatoryfunctions,isthepresenceofaTreg-speci-fichigher-orderregulatorynetwork[13,14,23].
Thepos-sibilitythatTreg-specificcontrolmechanismscanmaintainsustainedhighlevelsofFOXP3andcancon-troltheregulatoryfunctionhasbeenaddressedonlyrecentlywiththeidentificationoftheglycoprotein-Arepetitionspredominant(GARPorLRRC32)receptor[21,24-28].
IdentificationandcharacterizationofGARPasasafeguardofFOXP3GARPwasidentifiedbasedontheanalysisofgeneexpressionprofilingofTregandThcellsfollowingTCRstimulation,sinceTCRstimulationdoesleadtotheinductionoftheirmutuallyexclusivefunctions[21,24].
GARPisspecificallyinducedinCD4+CD25hiFOXP3hiTregcellsandthusisaTreg-specificactivationmarker[21,24-27].
BecausetheexpressionofGARPisup-regu-latedinFOXP3-transducedThcells,GARPobviouslydependsonFOXP3,andthisfindingsuggestsapotentialcontributiontotheregulatoryphenotype[21,29].
ThefunctionofGARPhasbeenelucidatedbyectopicover-expressioninhumanalloantigen-specificThcellsanddown-regulationofGARPinhumanantigen-speci-ficTregcells[21,29].
Retroviralover-expressionofGARPinThcells,aftersomeroundsofTCRstimulation,leadstoanefficientandstablereprogramming/transdifferen-tiationoftheestablishedeffectortowardtheregulatoryprogram.
ThisfindingisassociatedwithconstitutiveexpressionofFOXP3,theb-galactosidebindingproteinlectin,galactoside-binding,soluble,3(LGALS3)[8,30],andthecysteine-endoproteaselegumain(LGMN)[8]andwithanextendedTreg-signaturewithsuppressionofeffectorcytokineproductionandacquisitionofregula-toryfunctionssimilartothoseofTregcells[21,29].
Thus,aFOXP3-regulatinggenehasbeenidentifiedinthehumansystem,andthisfindingsuggeststhattheGARPsignalingpathwaymayhavedirecttherapeuticapplications[28,31]similartothosethathavebeendescribedforCD83inthemurinesystem[32].
Incontrast,lentiviraldown-regulationofGARPinhumanalloantigen-specificTregcellsbyspecificsmallinterferingRNA(siRNA)substantiallyimpairssuppres-sorfunctionandFOXP3expressionthatisassociatedwithimpairedinductionofCD83andCD27,bothknowntoregulateFOXP3[21,32,33].
Morestrikingisthefactthatsimilarchangesareinducedbythedown-regulationofFOXP3inTregcells,afindingthatpro-videscompellingevidenceforaGARP-FOXP3positivefeedbackloopinTregcells.
BecausethisfeedbackloopseemstobeinterrelatedwithotherFOXP3-regulatingsystemssuchasCD83andCD27,theexistenceofahigher-orderregulatorynetworkasdiscussedrecentlybyHori[13],canbespeculated(Figure1a).
Thus,GARPisaspecificmarkerofactivatedTregcellsandcanexplainthequalitativeandquantitativediffer-encesinFOXP3expressionandfunctioninTregcellsandThcells.
LackofGARPexpressionfurtherdiffer-entiatesandexplainsthetransientnatureofTGF-b-inducediTregcells[19],suggestingthatnaturalandiTregcellsmayrepresentalternativedifferentiationstagesofsuppressorcells[21,26].
Inlinewiththeseobservations,aspecificallyhypomethylatedregioninintron1ofGARPandtwodifferentiallymethylatedregionswithenhancerfunctionsinTregcellshaverecentlybeenchar-acterized.
Thesefindingshaveidentifiedanepigeneticbasisforthelineage-specificdifferenceinGARPexpres-sion[34].
GARPbringslatentTGF-bintoanewgameMembersoftheTGF-bfamilyarepleiotropiccytokineswithcrucialfunctionsindifferentiation,morphogenesis,andimmunehomeostasis.
TheirfunctioninimmunehomeostasisisevidencedbythefactthatdysregulationofTGF-bfunctionsisassociatedwithautoimmunity[35].
Likemanyothercelltypes,humanTregandThcellscansecretelatentTGF-b[20,36].
However,latency-associatedpeptide(LAP)preventstheactivationoflatentTGF-btowardtheactivematureTGF-b[37].
TheselectiveinductionofLAPandtheactivationofactiveTGF-buponTCRstimulationhasbeenreportedonlyforhumanTregcellsandclones[20,37,38].
ThisfindingfurtherexplainstheTGF-bspecifictranscrip-tionalsignatureanddetectionofexpressionofphos-phorylatedSMAD2inTregcellsofhumanandmurineorigin[20,23,37,39].
Moreover,specificup-regulationofLAPonactivatedhumanTregcellshasbeenshowntoallowimprovementsinthepurityofTregcellisolationproceduresbyseparatingactivatedLAP+FOXP3+TregcellsfromcontaminatingeffectorLAP-FOXP3+/loThcells[38].
Thus,besidesbeingamarkerofactivatedTregcellsincomplexwithLAP,TGF-b1isanimportantmodulatorofFOXP3expression[19,21,40],andapoten-tialmediatorofinfectioustolerancebyitsactionincon-vertingFoxP3-murineCD4+TcellsintofunctionalFoxP3+iTregcells[41].
Theissueofcell-surfacebindingofLAP/latentTGF-bonhumanTregcellshasbeenaddressedonlyrecentlywiththeidentificationofGARPasareceptorofthiscomplex[26,27].
Therefore,twoimportantregulatorycircuitsofTregcellscometogether:theGARP-FOXP3feedbackloopandtheautocrineTGF-bloop(Figure1b).
Withthat,thepotentialsynergyofmanyoftheTregsignaturecomponentsthatareessentialfortheregula-torypropertiesthathavebeenascribedtoTCRactiva-tion,interleukin-2,TGF-b,andFOXP3itself[20,23]couldbeexplainedbythisparticularspatiotemporalinterplayofinterrelatedsignalingsystemsonTregcells.
Probst-KepperandBuerBiologyDirect2010,5:8http://www.
biology-direct.
com/content/5/1/8Page2of6Figure1GARPassafeguardoftheregulatoryphenotype.
(A)Qualitative(lineage-specific)andquantitative(dose-effect)differencesinFOXP3expressioninhumanhelperTcells(Th;upperpanel)andregulatoryTcells(Treg;lowerpanel)areduetolineage-specificmethylationoftherespectiveloci(indicatedbyblackdots)andthustheexpressionofthegenesFOXP3andGARP.
InhumanTregcells,apositivefeedbackloophasbeenfoundbetweenGARPandFOXP3;thisfeedbackloopisinterrelatedwiththeFOXP3-enhancingmoleculesindicated.
PhosphorylationofLGALS3(indicatedbyaP)hasbeenreportedtobeessentialfortheFOXP3-regulatingfunction[21].
GARPisareceptorforLAP/latentTGF-b[26,27].
T-bet(T-boxexpressedinTcells),GATA3(GATA-bindingprotein3),RORg(retinoic-relatedorphanreceptorgamma)representtranscriptionfactorsofTh1,Th2,andTh17cells.
(B)ImplicationsforhumanandmurineTcells,respectively,oftheautocrineandparacrineeffectsofGARPandNrp1surface-boundLAP/latentTGF-bafteractivationofTGF-b.
TheTGF-bsignaturephospho-SMAD2(pSMAD2)hasbeenobservedinhuman(GARP+)andmurine(Nrp1+)Tregcells.
Paracrineeffectsincludethegenerationofinfectioustolerance.
(C)StructuralcompositionoftheLAP/latentTGF-bbindingproteinsNrp1andGARP(LRR,leucine-richrepeatdomain;CUB,complementsubcomponentsC1r/C1sdomain;F5/8coagulationfactordomain;MAM,meprin,A5,andreceptorprotein-tyrosinphosphataseμdomain;TM,transmembraneregion;L,leaderpeptide).
NIP(Nrp1interactingprotein)isaNrp1bindingproteininvolvedintheregulationofNrp1-mediatedsignalingasamolecularadapter[48].
Probst-KepperandBuerBiologyDirect2010,5:8http://www.
biology-direct.
com/content/5/1/8Page3of6Perspective:doesNrp1representafunctionalhomologueofGARPinmurineTregcellsTheidentificationofGARPasareceptorforLAP/latentTGF-bopensspeculationaboutapotentialcommondenominator.
Thereasonforsuchspeculationisthatneuropilin1(Nrp1),whichhasbeencharacterizedasamarkerofCD4+CD25+TregcellsinmicethatenhancesTregcell/dendriticcellcontactduringantigenrecogni-tion[42,43],hasalsobeencharacterizedasareceptorforLAP/latentTGF-b[39].
Moreover,murinesortedNrp1-TcellscapturesolubleNrp1(appliedasacon-stantfragment[Fc]-fusionprotein),andthecapturedNrp1increasestheirabilitytobindLAP/TGF-b1.
SuchcoatedTcellsacquirestrongregulatoryactivity[39].
Thus,Nrp1isaTGF-b1receptorthat,unlikeGARP[27],alsoactivatesthelatentformofTGF-b1.
ThestructuraldifferencesbetweenGARP,aToll-likereceptorhomologuewithleucine-richrepeats,andthemulti-domainproteinNrp1,areceptorforclass-3sema-phorin-familyproteinsandvascularendothelialgrowthfactor(Figure1c)[44],necessitatefurtherbiochemicalandmolecularanalysestoidentifyspecificbindinginter-actionsandpotentiallyassociatedmolecules.
TheissueofGARPexpressioninmurineTregcellsattheproteinlevelremainstobeelucidated.
DiscussionsOpenQuestionsConcerningtheFunctionofGARPBecauseGARPisconstitutivelyexpressedonplatelets[26,45],andbecauseapotentialfunctionofGARPonthrombusformationhasrecentlybeenreported[46],importantquestionsaboutGARPsignalingandparallelfunctioninplateletscomparedtoTregcellscouldbeconsidered.
ConcerningthedependenceofGARPexpressiononFOXP3asdescribedabove,ithasbeenreportedthatFOXP3isexpressedbyhumanandmurinemegakaryocytes[47].
Therefore,thethrombocytopeniaandplateletabnormalitiesexperiencedbysomepatientswithIPEXsyndromecanbeexplainedbylossoffunc-tionofFOXP3[47];however,thisexplanationwouldsuggestaconcomitantimpairmentofGARPexpressionandfunctiononIPEXplatelets,animpairmentthathasnotyetbeenshown.
Acontroversialissueisthepotentialsuppressorfunc-tionofGARP,suggestedrecently[24],becauseplateletsasanaturalsourceofGARP-expressingcellsdonotfunctionassuppressorcells[21].
Therefore,differencesinthefunctionofGARPinplateletsandTregcellscanbesuggested.
ThisquestionisimportantforthepotentialdesignofGARP-selectivedrugsthatcanspecificallytar-getonlyTregcellsandnotplateletfunctions.
Asofnow,neithertheligandnorthesignalingsystemorpotentialco-receptor(s)ofGARPhasbeenidentified,andidentify-ingthemisthemostimportantchallengeforthefuture.
ConclusionsTheidentificationofGARPasalineage-specifickeyreceptorofhumanactivatedTregcells,whichisinpartcontrolledbylineage-specifichypomethylationoftheGARPlocus,thecharacterizationofaGARP-FOXP3positivefeedbackloopthatsafeguardsFOXP3expres-sioninTregcells,andthebindingofLAP/latentTGF-btoGARPprovideaconceptualframeworkforanewmoleculardefinitionoftheregulatoryprogram.
IfGARPisareceptorforthewell-knownimmunemodulatorTGF-bonhumanTregcells,andifNrp1playsthissameroleonmurineTregcells,thenthissimilaritymightexplainthesimilaritiesintheTGF-bsignaturesthathavebeenobservedinTregcellsinbothspecies.
ThesurfacebindingandactivationofTGF-bhaveobviousimplicationsforinfectioustolerance.
Completeelucida-tionoftheGARP/GARP-ligandsignalingsysteminTregcellsandplateletsisanimportantchallengeandaprere-quisiteforthefuturedevelopmentofstrategiesandtoolsforinducingorinhibitingTregcellsinchronicinfection,tumorimmunotherapy,autoimmunediseases,andtransplantation.
ListofabbreviationsusedGARP:glycoprotein-Arepetitionspredominant;IPEX:immunedysregulation,polyendocrinopathy,enteropathy,X-linked;iTregcells:inducedregulatoryTcells;LAP:latency-associatedpeptide;Nrp1:neuropilin1;SMAD:Sma-andMad-relatedprotein2;TCR:T-cellreceptor;TGF-b:transforminggrowthfactor-b;Thcells:helperTcells;Tregcells:regulatoryTcells.
Reviewers'commentsReviewer'sreport1Reviewer1:Dr.
JimDiSanto,CytokinesandLymphoidDevelopmentLab,InstitutPasteur,Paris,FranceReviewer'scomment:IhavereadyourcommentforBiologyDirectentitled"FOXP3andGARP(LRRC32):themasteranditsminion".
IfindthiscommenttobeinterestingandsuitableforpublicationinBiologyDirect.
Idonothaveanyspecificcommentsforwebpublication.
Reviewer'sreport2Reviewer2:Dr.
BeneditaRocha,InstitutNationaldelaSantéetdelaRechercheMédicale(INSERM)U591,Insi-tutNecker,FranceReviewer'scomment:Regulatorycellshaveafunda-mentalroleinmanydiseaseprocesses,andextensiveexperimentalandclinicaldataindicatethattoolspre-ventingorincreasingregulatoryfunctionwillhaveafundamentaltherapeuticrole.
WhileFOXP3expressiongenerallycorrelateswithregulationinthemouse,thisisnotsoinhumanTcells.
ThiscommentreviewsaProbst-KepperandBuerBiologyDirect2010,5:8http://www.
biology-direct.
com/content/5/1/8Page4of6fundamentalaspect,thefactorsbesidesFOXP3expres-sionthatensuretheinductionofastableregulatoryfunctiononhumancells,theircorrelationwithFOXP3regulationandtheirpossiblemechanismsofaction.
Ifoundthetopicactualandimportant,thecommentclearandcomprehensiveandstronglysupportpublication.
Reviewer'sreport3Reviewer3:Dr.
WernerSolbach,InsituteforMedicalMicrobiologyandHygiene,UniversityLübeck,GermanyReviewer'scomment:Thems.
dealswiththeconnec-tivityofFOXP3and"glycoprotein-Arepititionspredo-minantreceptor(GARPorLRRC32)inthecontextofthefunctioningofregulatoryTcells(Tregs).
ThistopicisofgreatrelevanceinthecontextofclarifyingtheequivocalroleofFOXP3anditspartnersforexplanationofregulatoryTcellcircuits.
ItisclearthatnotonlyFOXP3orGARPalone,butalsolatentlyactivatedTGF-biscrucialforthesuppressiveactivityofTregcells.
TheauthorsnowverynicelybringtogethertheGARP-FOXP3regulatorycircuitwiththeautocrineTGF-bloopwhichhelpstoexplainmanyTregfeatures.
Intheirperspective,theyalsotrytoopenthoughtfulavenueshowtobringtogether(human)GARPwithitspossiblefunctionalhomologueinmice,neuropilin1.
Insum-mary,theypresentavaluableconceptualframeworkforunderstandingtheregulatoryprogramintheTcellreac-tivitysystemandbeyond.
Thems.
iswellwrittenandeasytounderstand.
IrecommendpublicationinBiologyDirect.
AcknowledgementsMichaelProbst-KepperwassupportedbygrantsfromtheVolkswagenStiftung(I/73234)andtheDeutscheForschungsgemeinschaft(PR554/2).
Authordetails1InstituteforMicrobiology,ImmunologyandHygiene,StdtischesKlinikumBraunschweiggGmbH,Braunschweig,Germany.
2InstituteforMedicalMicrobiology,UniversityHospitalEssen,Essen,Germany.
Authors'contributionsMPKandJBbothwereinvolvedindraftingofthemanuscriptandapprovedthefinalversiontobepublished.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
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