Chronicinfections,suchashumanimmunodeficiencyvirus,hepatitisCandBvirusesandcancers,including melanomaandnon-smallcelllungcancer,resultinwidespreadmorbidityandmortalityacrosstheglobe. Productiveimmuneresponsesarecriticalforthemaintenanceofhealthinpatientsafflictedwiththese diseases,yetchronicexposuretoantigenresultsinthefunctional?disarmament?ofrespondingTcells.This processistermed?exhaustion?andischaracterizedbythehierarchicallossofcytokineproduction,reductionin proliferativecapacityandconstitutiveexpressionofsurfaceinhibitoryreceptors.Overthepastdecade, significantprogresshasbeenmadeincharacterizingthetranscriptionfactors,inhibitoryreceptorsandsoluble mediatorsthatresultinthisprocess.Moreover,recentreportshavesuggestedthatchromatinaccessibilityand histonemodificationsmayplayasignificantroleinestablishingthisdysfunctionalphenotype.Yet,the molecularmechanismsthatinduceandregulateexhaustionarepoorlyunderstood.Therefore,inaneffortto guidethedevelopmentofnewandmoreeffectivetherapies,theprimarypurposeofthisproposalistoincrease ourunderstandingofthemechanismsthatinitiateandmaintainTcellexhaustionduringprotractedexposureto antigen. Utilizingcomputationalapproaches,wehaverecentlyidentifiedaparticularchromatin-associatedprotein,Tox, asapossiblekeyplayerinexhaustion.Amemberofthehigh-mobilitygroupproteins,Toxistheorizedtobindto DNA and modify local chromatin structure, resulting in significant changes in gene transcription. Though the proteinhasbeenshowntoplaycriticalrolesinthedevelopmentofNK,innate-likeandCD4Tcells,itsrolein regulatingperipheralresponsestoantigenareunexplored.Ourpreliminarydatashowsthatincontrasttoacute infection,whichresultsinthedownregulationofToxinperipheralTcells,chronicantigenexposureresultsina substantialincreaseintheexpressionofthisprotein.Thus,thethecentralhypothesizeofthisproposalis thatToxrespondstochronicantigenexposurebymodulatingthechromatinaccessibilityofregulatory regionsthatcontroltheexpressionoftranscriptionfactorsthatmediatethedysfunctionofexhaustion. Thestudiesdescribedwithinthisproposalarepoweredtoexplorethishypothesisandwillultimatelyelucidate theroleofToxingoverningdifferentialresponsestoacuteandchronicinfection.
Chronicinfectionsandcancerresultinsignificantmorbidityandmortalityworldwideandthehealthandsurvival ofpatientsafflictedwiththesediseasesisstronglydependentonthedevelopmentofrobustanddurableTcell responses.Unfortunately,theseillnessesarecommonlyassociatedwiththedevelopmentofdysfunctional immuneresponsesduetothe?exhaustion?ofrespondingTcells.Inanefforttoguidethedevelopmentof improvedfuturetherapies,thisproposalaimstoelevateourunderstandingofthemolecularmechanisms underlyingthedysfunctionseeninexhaustion.
| Bengsch, Bertram; Ohtani, Takuya; Khan, Omar et al. (2018) Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity 48:1029-1045.e5 |
| Kurachi, Makoto; Kurachi, Junko; Chen, Zeyu et al. (2017) Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nat Protoc 12:1980-1998 |
