Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen

[摘要] MaintenanceofbloodDChomeostasisisessentialtopreventingautoimmunitywhilecontrollingchronicinfection.However,theabilityofbacteremicpathogenstodirectlyregulatebloodDChomeostasishasnotbeendefined.Onesuchbacteremicpathogen,Porphyromonasgingivalis,isshownbyourgrouptosurvivewithinmDCsunderaerobicconditionsandtherein,metastasizefromitsoralmucosalniche.ThisisaccompaniedbyexpansionofthebloodmDCpoolinvivo,independentlyofcanonicalDCpoietins.WepresentlyknowlittleofhowthisbacteremicpathogencausesbloodDCexpansionandthepathophysiologicalsignificance.ThisworkshowsthatoptimumdifferentiationofMoDCsfromprimaryhumanmonocytes,withorwithoutGM‐CSF/IL‐4,isdependentoninfectionwithP.gingivalisstrainsexpressingtheDC‐SIGNligandmfa‐1.DCdifferentiationislostwhenDC‐SIGNisblockedwithitsligandHIVgp120orknockedoutbysiRNAgenesilencing.Thus,wehaveidentifiedanovel,noncanonicalpathwayofDCdifferentiation.WetermthesePDDCsandshowthatPDDCsarebonafideDCs,basedonphenotypeandphagocyticactivitywhenimmatureandtheabilitytoup‐regulateaccessorymoleculesandstimulateallo‐CD4+Tcellproliferationwhenmatured.ThelatterisdependentontheP.gingivalisstrainusedtoinitially“educate”PDDCs.Moreover,weshowthatP.gingivalis‐infected,conventionalMoDCsbecomeresistanttoapoptosisandinflammatorypyroptosis,asdeterminedbylevelsofAnnexinVandcaspase‐8,‐3/7,and‐1.Takentogether,weprovidenewinsightsintohowarelativelyasymptomaticbacteremiamayinfluenceimmunehomeostasisandpromotechronicinflammation...

[学科分类] 生理学

[关键词] inflammation;apoptosis;porphyromonas gingivalis;periodontal pathogen;T cells