Systemic delivery of IL‐27 by an adeno‐associated viral vector inhibits T cell‐mediated colitis and induces multiple inhibitory pathways in T cells

[摘要] IL‐27isaheterodimericcytokinethatiscomposedoftwosubunits,i.e.,EBV‐inducedgene3andIL‐27p28(alsoknownasIL‐30).AlthoughtheroleofendogenousIL‐27inthepathogenesisofautoimmunecolitis,anexperimentalmodelofhumaninflammatoryboweldisease,remainscontroversial,IL‐27localdeliveryhasbeenshowntoinhibitautoimmunecolitis.IL‐30hasbeenshowntoinhibitTh1andTh17responsesandisconsideredapotentialtherapeuticforcertainautoimmunediseases.Inthisstudy,wehavecomparedthetherapeuticefficacyofadeno‐associatedviralvector‐deliveredIL‐27andIL‐30inamurinemodelofautoimmunecolitis.Wefoundthat1singleadministrationofadeno‐associatedviralvector‐deliveredIL‐27,butnotadeno‐associatedviralvector‐deliveredIL‐30,nearlycompletelyinhibitedautoimmunecolitis.Adeno‐associatedviralvector‐deliveredIL‐27administrationinhibitedTh17responsesandinducedTcellexpressionofIL‐10,programmeddeathligand1,andstemcellantigen1.Intriguingly,adeno‐associatedviralvector‐deliveredIL‐27treatmentenhancedTh1responsesandinhibitedregulatoryTcellresponses.ExperimentsinvolvingtheadoptivetransferofIL‐10‐deficientTcellsrevealedthatadeno‐associatedviralvector‐deliveredIL‐27‐inducedIL‐10productionwasinsufficienttomediateinhibitionofautoimmunecolitis,whereasanti‐programmeddeath1antibodytreatmentresultedinthebreakingofadeno‐associatedviralvector‐deliveredIL‐27‐inducedTcelltolerance.Thus,systemicdeliveryofIL‐27inhibitsTh17responsesandinducesmultipleinhibitorypathways,includingprogrammeddeathligand1inTcells,andadeno‐associatedviralvector‐deliveredIL‐27,butnotIL‐30,mayhaveatherapeuticpotentialforthetreatmentofhumaninflammatoryboweldisease...

[学科分类] 生理学

[关键词] IL‐30;autoimmune colitis;PD‐L1;Th1/17;Tregs