ReviewTranscriptionFactorBhlhe40inImmunityandAutoimmunityMelissaE.Cook,1,4NicholasN.Jarjour,2,4Chih-ChungLin,3,4andBrianT.Edelson1,*Thebasichelix-loop-helixtranscriptionfactor(TF)Bhlhe40isemergingasakeyregulatorofimmunityduringinfection,autoimmunity,andinflammatoryconditions.WedescribetherolesofBhlhe40inthecirculatingandtissue-residentarmsoftheimmunesystem,withemphasisonrecentworkontheregulationofcytokinepro-ductionandproliferation.Weexplorethemechanismsbehindthesefunctionsinmousemodelsandhumancells,includinginteractionswithotherTFs,andproposethatBhlhe40isacentralmediatorofbothinflammationandpathogencontrol,aswellasacrucialregulatorofagrowingnumberoftissue-residentleukocytepopulations.Finally,wesuggestareasforfurtherstudythatmayadvanceourunderstandingofimmunityanddisease.Bhlhe40:AnEmergingRegulatorofImmunityBhlhe40(Box1)isamemberofthebasichelix-loop-helixTFfamily.Bhlhe40anditsmostcloselyrelatedfamilymember,Bhlhe41,bindtoclassBE-boxDNAsequenceswiththeconsensusmotifCACGTG[1,2].Theseproteinsoligomerizeasbothhomodimersandheterodimers[1–3].ManyfunctionsofmammalianBhlhe40havebeenidentified,includingregulatingcellcycling,celldeath,anddifferentiation,althoughthesestudieswerepredominantlyconductedincelllines[4].Bhlhe40/41aredistinctfromotherhelix-loop-helixOrangedomain-containingtranscriptionalrepressorsinthattheydonotinteractwiththecorepressorGroucho,butinsteadrepresstranscrip-tionbothincooperationwithhistonedeacetylases(HDACs)andinanHDAC-independentmanner[2,4].Bhlhe40alsohasapoorlyunderstoodpotentialfortranscriptionalactivation[5–8].Bhlhe40isexpressedinbothhematopoieticandnonhematopoieticmammaliancelltypes,andearlystudiesfocusedonitsrolebeyondtheimmunesystem[4,9].Bhlhe40−/−micewereinitiallygeneratedonamixedgeneticbackground,anddevelopedalate-onsetlymphoproliferativedisordercharacterizedbyenlargementoflymphoidorgansandimmunecellinfiltrationintoperipheraltissues[10].ThisphenotypewaslargelyduetofailuretoeliminateactivatedTandBcells.Weandothershaveobservedalesssevereand...
