Selective blockade of the inhibitory Fcγ receptor (Fcγ RIIB) in human dendritic cells and monocytes induces a type I interferon response program

The ability of dendritic cells (DCs) to activate immunity is linked to their maturation status. In prior studies, we have shown that selective antibody-mediated blockade of inhibitory Fc gamma RIIB receptor on human DCs in the presence of activating immunoglobulin (Ig) ligands leads to DC maturation and enhanced immunity to antibody-coated tumor cells. We show that Fc gamma receptor (Fc gamma R) - mediated activation of human monocytes and monocyte-derived DCs is associated with a distinct gene expression pattern, including several inflammation-associated chemokines, as well as type 1 interferon (IFN) response genes, including the activation of signal transducer and activator of transcription 1 (STAT1). Fc gamma R-mediated STAT1 activation is rapid and requires activating Fc gamma Rs. However, this IFN response is observed without a detectable increase in the expression of type I IFNs themselves or the need to add exogenous IFNs. Induction of IFN response genes plays an important role in Fc gamma R-mediated effects on DCs, as suppression of STAT1 by RNA interference inhibited Fc gamma R-mediated DC maturation. These data suggest that the balance of activating/inhibitory Fc gamma Rs may regulate IFN signaling in myeloid cells. Manipulation of Fc gamma R balance on DCs and monocytes may provide a novel approach to regulating IFN-mediated pathways in autoimmunity and human cancer.