TcellsdevelopandmatureinthethymusbeforeenteringthecirculationasnaiveTcells,whicharemaintainedbyTcellreceptor(TCR)engagementbyself-peptide–MHCmoleculesandthecytokineIL-7(ref.1).Onantigenstim-ulation,naiveTcellsdifferentiateintoeffectorTcellsandlong-livedmemoryTcells(TMcells).Poorresponsestopathogens,tumoursandvaccines,orthedevelopmentofimmunodeficiencyorautoimmunity,canariseifthenaiveTcellpoolisaltered.Therefore,itisimportanttounderstandhownaiveTcellsbalanceprosurvivalandactivationprogrammes2.NaiveTcellsareactivelymaintainedinaquiescentstate,whichisdefinedasbeingintheG0stageofthecellcycleandhavinglowmetabolic,transcriptionalandtranslationalactivities.ThisquiescentstatediffersfromtheperipheraltolerancethatisenforcedbyregulatoryTcells(Tregcells)orfromanergythatoccursduetoinappropriateTCRstimulationorcostimulation.NaiveTcellsarepoisedforactivationthatdrivestheirclonalexpansionandeffectorfunctions.Thisactivationismediatedbyaprocessknownasquiescenceexit,whichoccursafterantigenstimulationandcostimulationandbeforethefirstcelldivision3–5.Tcellfatedecisions,includingdifferentiationintoeffectorTcellsorTMcells,areoftenmadeduringthistimeframe5–8.QuiescenceexitofTcellsisdefinedbysix‘hallmarks’(listedinnoparticularorder)thatpromoteproliferation,survivalandeffectordifferentiation(asreviewedelsewhere9):cellcycleentryfromG0intoG2–S–Mphase;cellgrowth;autocrineorparacrineIL-2signalling;nutrientuptake;increasedanabolicmetabolism;andreprogrammingofmitochondrialmetabolism.ThisReviewsummarizesthemetabolicregulationofquiescenceandquiescenceexitinnaiveTcellsand,toalesserextent,quiescentTMcells.Wefirstdescribethemetabolicfeaturesofquiescenceandquiescenceexit.ThenwediscusshowTcellquiescenceisactivelymaintainedbyintracellularsignallingandmetabolicprogrammesandenforcedbyTregcell-derivedmecha-nisms.Nextwedetailhowmetabolicprogrammesdriveantigen-dependentactivationofnaiveTcellsandhownutrientsandothermicroenvironmentalfactorsregulatethebalancebetweenTcellquiescenceandactivation.Wethensumm...
