INHIBITION OF FC-GAMMA RECEPTOR-MEDIATED PHAGOCYTOSIS BY A NONPHAGOCYTIC FC-GAMMA RECEPTOR

There are three major classes of human Fc gamma receptors (Fc gamma RI , Fc gamma RII, and Fc gamma RIII) and various isoforms of each class are capable of mediating phagocytosis. Fc gamma RIIA is an unusual Fc gamma receptor in that it transmits a phagocytic signal in the absence of an additional receptor subunit. The cytoplasmic domain of Fc gamma RIIA contains a conserved motif containing two copies of the sequence YXXL. The tyrosines (Y) within the motif are phosphorylated after rec eptor crosslinking and the integrity of these conserved sequences is r equired for efficient phagocytosis. The Fc gamma RIIB receptors, Fc ga mma RIIB1 and Fc gamma RIIB2, contain one copy of the cytoplasmic YXXL sequence and do not transmit a phagocytic signal. In B cells, Fc gamm a IIB negatively regulates B-cell activation by the B-cell antigen rec eptor. Human macrophages express both Fc gamma RIIA and Fc gamma RIIB and while Fc gamma RIIA mediates phagocytosis, the function of Fc gamm a RIIB in these cells is unknown. Using the epithelial/fibroblast-like cell line COS-1 as a model to examine the molecular events that regul ate the phagocytosis of IgG-coated cells (EA), we investigated the eff ect of Fc gamma RIIB on Fc gamma RIIA signaling. Fc gamma RIIB inhibit ed phagocytosis mediated both by Fc gamma RIIA and by a chimeric Fc ga mma RIIA receptor containing the extracellular domain of Fc gamma RI a nd the trans membrane and cytoplasmic domains of Fc gamma RIIA. This i nhibition occurred at an early signaling stage because tyrosine phosph orylation of the Fc gamma RIIA cytoplasmic domain was inhibited after concurrent stimulation of these receptors with EA. Fc gamma RIIB mutat ions showed the importance of the Fc gamma RIIB YXXL for inhibition of Fc gamma RIIA-mediated phagocytosis. Deletion of the Fc gamma RIIB YX XL or conservative replacement of the YXXL tyrosine substantially redu ced the inhibitory signal. Fc gamma RIIB had a lesser inhibitory effec t on phagocytosis by the Fc gamma receptor Fc gamma RIIIA, which requi res a gamma subunit to mediate a phagocytic signal. These results show that Fc gamma RIIB negatively regulates phagocytic signaling by Fc ga mma RIIA and suggests that Fc gamma RIIB plays a role in modulating Fc gamma RIIA function in vivo. (C) 1998 by The American Society of Hema tology.