TLR‐activated conventional DCs promote γ‐secretase‐mediated conditioning of plasmacytoid DCs

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

关键词: human;    dendritic cells;    cooperation;    Notch;    CCL19;    γ;    ‐;    secretase;   

DOI  :  10.1189/jlb.0911452

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

CooperativeeventsbetweenDCsubsetsinvolvecellcontactandsolublefactors.Uponviralchallenge,murinepDCsinducecDCcooperationthroughCD40‐CD40LinteractionsandIL‐15secretion,whereasinhumans,thesameeffectismediatedbyIFN‐α.Conversely,duringbacterialinfections,pDCmaturationmaybeinducedbyactivatedcDCs,althoughnomechanismshadbeendescribedsofar.Here,weinvestigatehowhumanpDCsare“conditioned”bycDCs.Blood‐borneDCsubsets(cDCsandpDCs)weresortedfromhealthydonors.IL‐3‐maintainedpDCswerecoculturedwithLPS‐activated,poly(I:C)‐activated,orcontrolcDCs[cDCLPS,cDCP(I:C),cDCCTRL].CocultureexperimentsshowedthatcDCLPS‐conditionedpDCsup‐regulatedmaturationmarkers,suchasCD25andCD86,whereasSNscontainedhigheramountsofIL‐6andCCL19comparedwithcontrolconditions.Gene‐expressionanalysesonsortedcDCLPSorcDCP(I:C)conditionedpDCsconfirmedtheinductionofseveralgenes,includingIL‐6andCCL19andremarkably,severalNotchtargetgenes.Furtherstudiesusingtheγ‐secretase/NotchinhibitorDAPTandsolubleNotchligandsresultedinasignificantlyreducedexpressionofcanonicalNotchtargetgenesinconditionedpDCs.DAPTtreatmentalsohamperedthesecretionofCCL19(butnotofIL‐6)bycDCLPSconditionedpDCs.Theseresultsrevealtheinvolvementofγ‐secretase‐mediatedmechanisms,includingtheNotchpathway,inthecellcontact‐dependentcommunicationbetweenhumanDCsubsets.TheresultingpartialactivationofpDCsafterencounteringwithmaturecDCsendowspDCswithanaccessoryfunctionthatmaycontributetoTcellrecruitmentandactivation...

【 授权许可】

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