Inhibition of Fc g Receptor - Mediated Phagocytosis by a Nonphagocytic Fc g Receptor

There are three major classes of human Fcg receptors (FcgRI, FcgRII, and FcgRIII) and various isoforms of each class are capable of mediating phagocytosis. FcgRIIA is an unusual Fcg receptor in that it transmits a phagocytic signal in the absence of an additional receptor subunit. The cytoplasmic domain of FcgRIIA contains a conserved motif containing two copies of the sequence YXXL. The tyrosines (Y) within the motif are phosphorylated after receptor crosslinking and the integrity of these conserved sequences is required for efficient phagocytosis. The FcgRIIB receptors, FcgRIIB1 and FcgRIIB2, contain one copy of the cytoplasmic YXXL sequence and do not transmit a phagocytic signal. In B cells, FcgRIIB negatively regulates B-cell activation by the B-cell antigen receptor. Human macrophages express both FcgRIIA and FcgRIIB and while FcgRIIA mediates phagocytosis, the function of FcgRIIB in these cells is unknown. Using the epithelial/fibroblast-like cell line COS-1 as a model to examine the molecular events that regulate the phagocytosis of IgG-coated cells (EA), we investigated the effect of FcgRIIB on FcgRIIA signaling. FcgRIIB inhibited phagocytosis mediated both by FcgRIIA and by a chimeric FcgRIIA receptor containing the extracellular domain of FcgRI and the transmembrane and cytoplasmic domains of FcgRIIA. This inhibition occurred at an early signaling stage because tyrosine phosphorylation of the FcgRIIA cytoplasmic domain was inhibited after concurrent stimulation of these receptors with EA. FcgRIIB mutations showed the importance of the FcgRIIB YXXL for inhibition of FcgRIIA-mediated phagocytosis. Deletion of the FcgRIIB YXXL or conservative replacement of the YXXL tyrosine substantially reduced the inhibitory signal. FcgRIIB had a lesser inhibitory effect on phagocytosis by the Fcg receptor FcgRIIIA, which requires a g subunit to mediate a phagocytic signal. These results show that FcgRIIB negatively regulates phagocytic signaling by FcgRIIA and suggests that FcgRIIB plays a role in modulating FcgRIIA function in vivo. r 1998 by The American Society of Hematology.