43: Type I interferon promotes FLT3 ligand-dependent plasmacytoid dendritic cell development from common lymphoid progenitor

Abstract

Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon (IFN-I) producing cells during infections and inflammation. While cDCs can be generated from either myeloid or lymphoid lineages, the developmental origin and signals controlling pDC development remain elusive. Here, we report a synergistic role for IFN-I and Flt3 ligand (FL) in pDC development from common lymphoid progenitors (CLPs). Both conventional DCs (cDCs) and pDCs were generated from CLPs in response to FL, while pDC generation required higher concentrations of FL and concurrent IFN-I signaling. An absence of IFN-I receptor or impairment of IFN-I signaling significantly impeded pDC development from CLPs. Competitive adoptive transfer showed that the defective pDC development was intrinsic to the loss of IFN-I signaling in CLPs. Interestingly, Flt3 expression was reduced in Ifnar1 −/− CLPs as opposed to WT CLPs. Concomitantly, FL-activated signaling, proliferation and survival of CLPs were attenuated in the absence of IFNAR1. Restoration of Flt3 expression in Ifnar1 −/− CLPs rescued pDC development. FL also enhanced Flt3 expression on CLPs in an IFN-I-dependent manner. Furthermore, FL induced IFN-I production in CLPs. While exogenous IFN-I augmented pDC generation, neutralization of IFNAR1 blocked pDC formation from WT CLPs. The dose-dependent effect of FL on DC homeostasis supports the instructive model, at least, for CLPs. Collectively; these results define a critical role for the FL/IFN-I/Flt3 axis in pDC differentiation from CLPs and identify a potential target for therapeutic intervention in inflammatory and autoimmune diseases associated with pDCs.