SHIP negatively regulates Flt3L‐derived dendritic cell generation and positively regulates MyD88‐independent TLR‐induced maturation

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

关键词: differentiation;    cytokines;    maturation;    T cell activation;   

DOI  :  10.1189/jlb.1209825

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

WedemonstratehereinthatSHIPnegativelyregulatestheproliferation,differentiation,andsurvivalofFL‐DCsfromBMprecursors,asshownbyamorerapidappearanceandhighernumbersofCD11c+DCsfromSHIP−/−culturesaswellasincreasedsurvivalofmatureFL‐DCsintheabsenceofFlt3L.Thisincreasedsurvival,whichislostwithlowlevelsofthePI3Kinhibitor,LY,correlateswithanenhancedconstitutiveactivationoftheAktpathway.Interestingly,however,theseSHIP−/−FL‐DCsdisplayaless‐maturephenotypeafterTLRligandstimulation,asfarasMHCII,CD40,andCD86areconcerned.Unexpectedly,SHIP−/−FL‐DCsactivatedwithTLRligands,whichuseMyD88‐independentpathways,aremarkedlyimpairedintheirabilitytostimulateAg‐specificTcellproliferation,andSHIP−/−FL‐DCsactivatedbyTLRs,whichexclusivelyusetheMyD88‐dependentpathway,areascapableasWTFL‐DCs.ThereisalsoamorepronouncedTH1skewingbytheSHIP−/−FL‐DCsthanbyWTFL‐DCs,whichisconsistentwithourfindingthatSHIP−/−FL‐DCssecretehigherlevelsofIL‐12andTNF‐αinresponsetoLPSordsRNAthantheirWTcounterparts.TheseresultssuggestthatSHIPnegativelyregulatesFL‐DCgenerationbutpositivelyregulatesthematurationandfunctionofFL‐DCsinducedbyTLRs,whichoperateviaMyD88‐independentpathways...

【 授权许可】

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