CD8+ dendritic cell‐mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L

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

关键词: type 1 diabetes;    DEC‐;    205;    CD40;    peripheral tolerance;   

DOI  :  10.1189/jlb.0113013

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

DCsareimportantmediatorsofperipheraltoleranceforthepreventionofautoimmunity.ChimericαDEC‐205antibodieswithattachedantigensallowinvivoantigen‐specificstimulationofTcellsbyCD8+DCs,resultingintoleranceinnonautoimmunemice.However,itisnotclearwhetherDC‐mediatedtoleranceinductionoccursinthecontextofongoingautoimmunity.WeassessedtheroleofCD8+DCsinstimulationofautoreactiveCD4+TcellsintheNODmousemodeloftype1diabetes.TargetingofantigentoCD8+DCsviaαDEC‐205ledtoproliferationandexpansionofβ‐cellspecificBDC2.5Tcells.TheseTcellsalsoproducedIL‐2andIFN‐γanddidnotup‐regulateFoxP3,consistentwithanactivatedratherthantolerantphenotype.Similarly,endogenousBDCpeptide‐reactiveTcells,identifiedwithI‐Ag7tetramers,didnotbecometolerantafterantigendeliveryviaαDEC‐205:nodeletionorTreginductionwasobserved.WeobservedthatCD8+DCsfromNODmiceexpressedhighersurfacelevelsofCD40thanCD8+DCsfromC57BL/6mice.BlockadeofCD40–CD40LinteractionsreducedthenumberofBDC2.5Tcellsremaininginmice,10daysafterantigentargetingtoCD8DCs,andblockedIFN‐γproductionbyBDC2.5Tcells.ThesedataindicatethattheabilityofautoreactiveCD4+TcellstoundergotolerancemediatedbyCD8+DCsisdefectiveinNODmiceandthatblockingCD40–CD40Linteractionscanrestoretoleranceinduction...

【 授权许可】

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