Protection of CD4+ T cells from hepatitis C virus infection‐associated senescence via ΔNp63–miR‐181a–Sirt1 pathway

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: T cell senescence;    hepatitis C;    microRNA‐;    181a;    transcription factor p63;    Sirtuin 1;   

DOI  :  10.1189/jlb.5A0316-119RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Tcelldysfunctionhasacrucialroleinestablishingandmaintainingviralpersistence.WehavepreviouslyshownadeclineinmiR‐181a,whichregulatesCD4+TcellresponsesviaDUSP6overexpression,inindividualswithhepatitisCvirus(HCV)infection.Here,wedescribeacceleratedTcellsenescenceinHCV‐infectedindividualscomparedwithage‐andsex‐matchedhealthysubjects.Mechanisticstudiesrevealedthatup‐regulationoftranscriptionfactorΔNp63ledtothedeclineofmiR‐181aexpression,resultinginanoverexpressionoftheantiagingproteinSirt1,inCD4+TcellsfromHCV‐infectedindividuals.EitherreconstitutingmiR‐181aorsilencingΔNp63orSirt1expressioninCD4+TcellsledtoacceleratedTcellsenescence,asevidencedbyanincreasedsenescence‐associatedβ‐galactosidase(SA‐β‐gal)expression,shortenedtelomerelength,anddecreasedEdUincorporation;thissuggeststhatHCV‐inducedTcellsenescenceiscounterregulatedbytheΔNp63–miR‐181a–Sirt1pathway.AnincreaseofIL‐2productionwasobservedinthesesenescentCD4+TcellsandwasdrivenbyamarkedlyreducedfrequencyofFoxp3+regulatoryT(Treg)cellsandincreasednumberofFoxp3−effectorT(Teff)cellsuponmanipulatingtheΔNp63–miR‐181a–Sirt1pathway.Inconclusion,thesefindingsprovidenovelmechanisticinsightsintohowHCVusescellularsenescentpathwaystoregulateTcellfunctions,revealingnewtargetsforrejuvenatingimpairedTcellresponsesduringchronicviralinfection...

【 授权许可】

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