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Download FOR IMMEDIATE RELEASE Exhausted T cells LJI researchers map
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FORIMMEDIATERELEASE ExhaustedTcells LJIresearchersmapgenome-widechangesthatdriveTcellmaturationandexhaustion December19,2016 LAJOLLA,CA—InabidtobetterunderstandthegeneexpressionpatternsthatcontrolT cellactivity,researchersattheLaJollaInstituteforAllergyandImmunologymapped genome-widechangesinchromatinaccessibilityasTcellsrespondtoacuteandchronic virusinfections.Theirfindings,publishedintheDec.20,2016issueofImmunity,shed lightonthemolecularmechanismsthatdeterminethefateofTlymphocytesandopen newapproachestoclinicalinterventionstrategiestomodulateTcellactivityand improveimmunefunction. “IdentifyingthedifferentfactorsthatdeterminedifferentTcellstatesandtherefore theirfunctionhelpsusunderstandifTcellswillbeableornottofightviralinfectionsor tumorgrowth,andiftheywillbeableornottoprovidelong-termprotection,”saysthe study’sfirstauthorJamesScott-Browne,apostdoctoralfellowinthelaboratoryof AnjanaRao,aprofessorintheDivisionofSignalingandGeneExpression.“Wemaybe abletoreverttheexhaustionphenotypeofTcellsandrenderthembetterabletofight tumorsorchronicviralinfectionssuchasHIV,orgeneratebettermemorycellsin responsetovaccines.” Whenvirusesinvadeorcellsturnmalignant,theimmunesystemmobilizesasmall cohortofnaïveorimmatureCD8Tcells,acrucialsubdivisionoftheimmunesystem chargedwithkillingvirus-infectedandcancerouscells.Uponactivation,theymature andproliferateexponentiallyintohighlyspecificeffectorTcellsthateliminatevirusinfectedorotherwisecompromisedcells.Aftertheirjobisdone,mosteffectorTcells dieleavingbehindonlyasmallcontingentofmemoryTcellthatconferlong-term protection. InthefaceofchronicviralinfectionssuchashepatitisandHIVaswellascertaintypesof cancers,however,activatedCD8Tcellsareunabletogaintheupperhandandclearthe threat.Asaresult,CD8Tcellsstarttoexpressinhibitorycellsurfacereceptorsthat transmitinhibitorysignalsintothecellestablishinganegativefeedbackloop.The mechanismisdesignedtopreventexcessiveimmuneresponsesfromtakingholdbutit leavesCD8Tcellsunabletofightforeigninvaderseffectivelyandforcesthemintoa stateknownas“Tcellexhaustion.” Inearlierwork,RaoandherteamhadpinpointedatranscriptionfactorknownasNFAT asthemolecularlinchpinthatorchestratesTcellactivationandexhaustion.WhentheT cellreceptoronthesurfaceofCD8Tcellsrecognizesaforeignprotein,itkicksoffa signalingcascadethatculminatesintheactivationofNFATanditspartnerAP-1. Together,thepairbindstoregulatoryregionsinthegenomeandinitiatesagenetic programthatactivatesTcellsandreadiesthemtofightcancerandviralinfections. Whenactingonitsown,NFATshiftstheequilibriumfromanactivatedtoanexhausted statebybindingtoadifferentsubsetofregulatoryregionswithinthegenome,impairing theimmunesystem’sresponsetotumorsandinfection. Thecurrentstudyexpandsthepreviousexperiments,whichwerelargelybasedonlabgrownTcells,toTcellsisolatedfrommicewithacuteorchronicviralinfections.It centeredonapowerfulmethodologyknownasATAC-seq,whichpinpoints“open”or accessiblestretchesofchromatin.ChromatinisthesumtotalofgenomicDNAandall associatedproteins,whichnotonlypackagesandcondensesDNAbutalsohelpscontrol geneexpressionbygivingordenyingaccesstotranscriptionfactors.Knowingwhich regulatorysitesinthegenomeareopenforbusinessallowsscientiststoconcludewhich transcriptionfactorsplayaroleincertainbiologicalprocesses. “Weshowedthatwhennaïvecellsaretransformedintoeffectorcells,therearebig changesintheregionsofchromatinnearthegenesthatdeterminean“activatedfate”, explainsco-leadauthorRenataPereira,formerlyapostdoctoralresearcherintheRao laboratory,andnowanassistantprofessorattheUniversidadeFederaldoRiode JaneiroinBrazil.“Incontrastthechromatinstructureofeffectorcellsisquitesimilarto thatinmemoryorexhaustedcells,suggestingthatthedifferencesinthefunctionsof thesecelltypesdependmostlyontheactionoftranscriptionfactorsthatbindthe alreadyopenchromatinregions.Sotranscriptionfactorscouldbeamoreinteresting targettomodulatethefunctionofTcellsthanproteinsthatmodulateifthechromatin ismoreorlessaccessible.” TheworkwasfundedbytheNationalInstitutesofHealth(R01AI40127)(toA.R.).the DamonRunyonCancerResearchFoundation,andthePewLatinAmericanFellows ProgramintheBiomedicalSciences. Fullcitation:"Genome-widechangesinchromationaccessibilityinCD8Tcellsduring viralinfection.”JamesP.Scott-Browne,IsaacF.López-Moyado,SaraTrifari,Victor Wong,LukasChavez,AnjanaRao,andRenataMPereira.Immunity,2016. DOI:10.1016/j.immuni.2016.10.028 URL:http://www.cell.com/immunity/fulltext/S1074-7613(16)30439-3. AboutLaJollaInstituteforAllergyandImmunology TheLaJollaInstituteforAllergyandImmunologyisdedicatedtounderstandingthe intricaciesandpoweroftheimmunesystemsothatwemayapplythatknowledgeto promotehumanhealthandpreventawiderangeofdiseases.Sinceitsfoundingin1988 asanindependent,nonprofitresearchorganization,theInstitutehasmadenumerous advancesleadingtowarditsgoal:lifewithoutdisease. Mediacontact: JessicaRoi [email protected] 858.752.6645(office)
