Regulation of immune responses and tolerance the m

Chang-ZhengChenStevenSchaffertRitaFragosoChristinaLohRegulationofimmuneresponsesandtolerance:themicroRNAperspectiveAuthors’addressesChang-ZhengChen1,2,StevenSchaffert1,2,RitaFragoso1,2,ChristinaLoh1,21DepartmentofMicrobiologyandImmunology,StanfordUniversitySchoolofMedicine,Stanford,CA,USA.2DepartmentofMicrobiologyandImmunology,BaxterLaboratoryinStemCellBiology,StanfordUniversitySchoolofMedicine,Stanford,CA,USA.Correspondenceto:Chang-ZhengChenDepartmentofMicrobiologyandImmunologyBaxterLaboratoryinStemCellBiology,StanfordUniversitySchoolofMedicine269CampusDriveCCSR3205BStanford,CA94305,USATel.:[phone]Fax:[phone]e-mail:[e-mail]NIHgrants(1R01AI073724and1DP1OD00643501)toC.-Z.C.,aStanfordGraduatefellowshiptoS.S.,aFundac
~aoparaaCi^enciaeaTecnologiafellowship(POPH/FSE/SFRH/BPD/43526/2008)toR.F.,andaCHIRFellowshiptoC.L.Theauthorshavenoconflictsofinteresttodeclare.ThisarticleispartofaseriesofreviewscoveringRNARegulationoftheImmuneSystemappearinginVolume253ofImmunologicalReiews.Summary:Muchhasbeenlearnedaboutthemolecularandcellularcomponentscriticalforthecontrolofimmuneresponsesandtoler-ance.Itremainsachallenge,however,tocontroltheimmuneresponseandtoleranceatthesystemlevelwithoutcausingsignificanttoxicitytonormaltissues.RecentstudiessuggestthatmicroRNA(miRNA)genes,anabundantclassofnon-codingRNAgenesthatpro-ducecharacteristicapproximately22nucleotidessmallRNAs,playimportantrolesinimmunecells.Inthisarticle,wediscussemergingknowledgeregardingthefunctionsofmiRNAgenesintheimmunesystem.WedelveintotherolesofmiRNAsinregulatingsignalingstrengthandthreshold,homeostasis,andthedynamicsoftheimmuneresponseandtoleranceduringnormalandpathogenicimmunologicalconditions.WealsopresentobservationsbasedonanalyzesofmiR-181familygenesthatindicatethepotentialfunctionsofprimaryand/orprecursormiRNAsintargetrecognitionandexploretheimpactofthesefindingsontargetidentification.Finally,weillustratethatdespitethesubtleeffectsofmiRNAsongeneexpression,miRNAshavethepotentialtoinfluencetheoutcomesofnormalandpathogenicimmuneresponsesbycontrollingthequantitativeanddynamicaspectsofimmuneresponses.TuningmiRNAfunctionsinimmunecells,throughgain-andloss-of-functionapproachesinmice,mayrevealnovelapproachtorestoreimmuneequilibriumfrompathogeniccon-ditions,suchasautoimmunediseaseandleukemia,withoutsignificanttoxicity.Keywords:microRNA,miR-181,leukemia,hematopoiesis,autoimmunity,T-cellreceptorsIntroductionTheimmunesystemmediatesdynamicinteractionsbetweenanimalsandtheirenvironment.Throughoutananimal’slife-time,theimmunesystemplayscriticalrolesinmaintaininghomeostasisanddefendingagainstinvadingpathogens.Tomaintainhomeostasis,theimmunesystemmustprovidesta-bilityandwithstandchallenges.Simultaneously,todefendagainstinvadingpathogens,theimmunesystemmustpos-sesstheabilitytomountrapidandspecificresponsesandtodevelopandmaintainmemoriesofinvaders.Moreover,theimmunesystemmusthavebuilt-inmechanismsthatallowittodistinguishselffromforeignantigens.DysregulationofImmunologicalReviews2013Vol.253:112–128PrintedinSingapore.Allrightsreserved©2013JohnWiley&SonsA/S.PublishedbyBlackwellPublishingLtdImmunologicalReviews0105-2896©2013JohnWiley&SonsA/S.PublishedbyBlackwellPublishingLtd112ImmunologicalReviews253/2013theimmunesystemresultsinvariouspathologicaldisordersincludingdefectsinhost–pathogeninteractions,autoim-munedisease,andcancer.Howtheimmunesystemencom-passestheseinterestingproperties–someseeminglycontradictory–andhowtorestoreadysfunctionalimmunesystemtothehealthystatehavecaptivatedtheimaginationsofimmunologistsformanydecades.Muchhasbeenlearnedaboutthemolecular,cellular,andorganismalcomponentsoftheimmunesystemandthefunc-tionsofthesecomponentsinimmuneresponsesandtoler-ance.Atthemolecularlevel,thefocusofmoststudieshasbeenonprotein-codinggenes.ThediscoveryofmicroRNA(miRNA)genesrevealedanunexpectedlayerofgeneticprogramsthatregulatetheimmuneresponseatthepost-transcriptionallevels(1,2).Thenon-codingRNAsproducedfrommiRNAgeneshavewidespreadeffectsongeneexpres-sionbyinfluencingtargetmRNAstabilityand/ortranslationalefficiency.EmergingevidenceindicatesthatmiRNAplayimportantrolesindiversebiologicalprocesses(reviewedin3,4),andanumberofrecentreviewshavesummarizedthegrowingbodyofknowledgeregardingmiRNAfunctionsinimmunecells(5–7).Inthisreview,weexaminetheimpactofmiRNAsonimmuneresponseandtoleranceatthemolecular,cellular,andsystemlevelswithafocusongeneticanalysesinmice.DiversefunctionsofanimalmiRNAsThediscoveryofthefirstmiRNAgene,lin-4,anditsregula-torycontroloflin-14mRNAatthetranslationalleveldefinedtheessentialcharacteristicsofapreviouslyunsuspectedformofRNAregulatorsandmodeofgeneregulation(8,9).TheimportanceofmiRNAgenesonlybecameapparentfollow-ingtheidentificationofanotherlin-4-likenon-codingRNAgene,let-7,andthediscoveryofRNAinterference(10,11).let-7controlsthetimingofC.eleganscelllineagedevelopmentduringthelaterlarvaltoadulttransitionthroughsuppres-sionoftheexpressionoflin-41targetmRNAs.Unlikelin-4,thematurelet-7miRNAis