Autophagyisahighlyevolutionarilyconservedmecha-nismfortherecyclinganddegradationofcytoplasmicconstituents(Box1).Autophagosomeswithadoublemembraneformaroundportionsofthecytoplasm,engulftheircargoandthenfusewithlysosomes,wheretheircontentsaredegradedandrecycled1.Autophagyisactivatedbyarangeofenvironmentalconditions,suchaschangesinoxygenandnutrientavailability,butalsohormones,cytokines,growthfactorsandreceptorengagement,whichinitiatecellulardifferentiationorexitfromquiescence.Themechanismsbywhichautophagyinfluencescellulardifferentiationareonlypartiallyexplored.Broadly,autophagymayselectivelydegradeproteinsthatregulatethedifferentiationstatusordif-ferentiationpathwaysofspecificcellpopulations,suchastranscriptionfactorsandtheirregulators,orcellcycleproteins2.However,itremainschallengingtodeterminewhichofthemanypotentialsubstratesofautophagyareselectivelytargetedtomediatedifferentiationratherthanbeingpassivelydegraded.Autophagymayalsopartici-pateincellularremodellingthroughtheremovalandrecyclingofsurplusorganelles.Autophagyasasourceofmetabolites,suchasfreefattyacids(FFAs),mayalsobecrucialtosupplytheenergyormacromoleculesthatarerequiredfordifferentiation3(Fig.1).Typically,cellsthatdependonoxidativephosphorylation(OXPHOS)—forexample,memorylymphocytesorregulatoryT(Treg)cells—aremostlikelytorequireautophagyfortheirhomeostasis4–7.Itisnotunderstoodwhythisisthecase,butitmightbeowingtothehighlevelofmitochondrialactivityinthesecellsandthere-foreanincreasedrequirementtocontrolmitochondrialqualitybyautophagy.Ifautophagyispreventedinthesecelltypes,OXPHOSisimpairedowingtodefectivemito-chondrialfunction,andaswitchtoaerobicglycolysisoccursincompensation4,8,9.Cellsthatpreferentiallyuseaerobicglycolysis,suchaseffectorTcells,tendtobelessaffectedwhenautophagyisdefective.Outsideoftheimmunesystem,therearemanywell-studiedexamplesofautophagyhavingacrucialroleindeterminingcellulardifferentiation.Forexample,duringerythropoiesis,precursorreticulocytesmusteliminatetheirorganellesastheybecome...
