602|NATURE|VOL548|31AUgUsT2017LETTERdoi:10.1038/nature23665HomeostaticcontrolofmetabolicandfunctionalfitnessofTregcellsbyLKB1signallingKaiYang1,DanielBastardoBlanco1,geoffreyNeale2,PeterVogel3,JulianAvila4,ClaryB.Clish4,ChuanWu5,sharadshrestha1,sherriRankin1,LingyunLong1,AnilKC1&HongboChi1RegulatoryTcells(Tregcells)haveapivotalroleintheestablishmentandmaintenanceofimmunologicalself-toleranceandhomeostasis1,2.TranscriptionalprogrammingofregulatorymechanismsfacilitatesthefunctionalactivationofTregcellsinthepreventionofdiversetypesofinflammatoryresponses3,4.ItremainsunclearhowTregcellsorchestratetheirhomeostasisandinterplaywithenvironmentalsignals.HereweshowthatliverkinaseB1(LKB1)programsthemetabolicandfunctionalfitnessofTregcellsinthecontrolofimmunetoleranceandhomeostasis.MicewithaTreg-specificdeletionofLKB1developedafatalinflammatorydiseasecharacterizedbyexcessiveTH2-type-dominantresponses.LKB1deficiencydisruptedTregcellsurvivalandmitochondrialfitnessandmetabolism,butalsoinducedaberrantexpressionofimmuneregulatorymoleculesincludingthenegativeco-receptorPD-1andtheTNFreceptorsuperfamilyproteinsGITRandOX40.Unexpectedly,LKB1functioninTregcellswasindependentofconventionalAMPKsignallingorthemTORC1–HIF-1αaxis,butcontributedtotheactivationofβ-cateninsignallingforthecontrolofPD-1andTNFreceptorproteins.BlockadeofPD-1activityreinvigoratedtheabilityofLKB1-deficientTregcellstosuppressTH2responsesandtheinterplaywithdendriticcellsprimedbythymicstromallymphopoietin.Thus,TregcellsuseLKB1signallingtocoordinatetheirmetabolicandimmunologicalhomeostasisandtopreventapoptoticandfunctionalexhaustion,therebyorchestratingthebalancebetweenimmunityandtolerance.ThetumoursuppressorLKB1(encodedbyStk11)isabioenergeticsensorthatcontrolscellmetabolismandgrowth5.TodefinetheroleofLKB1inTregcells,wecrossedmicecarryingloxP-flankedStk11alleles(Stk11fl/fl)withFoxp3YFP-cre(Foxp3cre)mice6tospecificallydeleteStk11inTregcells(denotedhereafterasFoxp3creStk11fl/flmice)(ExtendedDataFig.1a).ComparedwithFoxp3...
