Role of the P2Y12 Receptor in the Modulation of Murine Dendritic Cell Function by ADP

Abstract

The effects of ADP on the biology of dendritic cells have been studied much less than those of ATP or adenosine. In this study, we showed that adenosine-5′-O-(2-thiodiphosphate) (ADPβS) induced intracellular Ca2+ transients in murine dendritic cells (DCs). This effect was abolished by AR-C69931MX, a dual P2Y12 and P2Y13 receptor antagonist. RT-PCR experiments revealed the expression of both P2Y12 and P2Y13 mRNA in DCs. The Ca2+ response to ADPβS was maintained in P2Y13-deficient DCs, whereas it was abolished completely in P2Y12−/− DCs. ADPβS stimulated FITC-dextran and OVA capture in murine DCs through macropinocytosis, and this effect was abolished in P2Y12−/− DCs. ADPβS had a similar effect on FITC-dextran uptake by human monocyte-derived DCs. OVA loading in the presence of ADPβS increased the capacity of DCs to stimulate OVA-specific T cells, whereas ADPβS had no effect on the ability of DCs to stimulate allogeneic T cells. Moreover, after immunization against OVA, the serum level of anti-OVA IgG1 was significantly lower in P2Y12−/− mice than that in wild-type controls. In conclusion, we have shown that the P2Y12 receptor is expressed in murine DCs and that its activation increased Ag endocytosis by DCs with subsequent enhancement of specific T cell activation.