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Inhibition of Fc Receptor-Mediated Phagocytosis by a
Nonphagocytic Fc Receptor
Sharon Hunter,
Zena K. Indik,
Moo-Kyung Kim,
M. Danielle Cauley,
Jong-Gu Park, and
Alan D. Schreiber
From the Hematology and Oncology Division, University of Pennsylvania
School of Medicine, Philadelphia.
There are three major classes of human Fc receptors (FcRI,
FcRII, and FcRIII) and various isoforms of each class are capable of mediating phagocytosis. FcRIIA is an unusual Fc receptor in
that it transmits a phagocytic signal in the absence of an additional
receptor subunit. The cytoplasmic domain of FcRIIA 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 FcRIIB receptors, FcRIIB1 and
FcRIIB2, contain one copy of the cytoplasmic YXXL sequence and do
not transmit a phagocytic signal. In B cells, FcRIIB negatively
regulates B-cell activation by the B-cell antigen receptor. Human
macrophages express both FcRIIA and FcRIIB and while FcRIIA
mediates phagocytosis, the function of FcRIIB 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 FcRIIB on
FcRIIA signaling. FcRIIB inhibited phagocytosis mediated both by
FcRIIA and by a chimeric FcRIIA receptor containing the
extracellular domain of FcRI and the transmembrane and cytoplasmic domains of FcRIIA. This inhibition occurred at an early signaling stage because tyrosine phosphorylation of the FcRIIA cytoplasmic domain was inhibited after concurrent stimulation of these receptors with EA. FcRIIB mutations showed the importance of the FcRIIB YXXL for inhibition of FcRIIA-mediated phagocytosis. Deletion of the
FcRIIB YXXL or conservative replacement of the YXXL tyrosine substantially reduced the inhibitory signal. FcRIIB had a lesser inhibitory effect on phagocytosis by the Fc receptor FcRIIIA, which requires a subunit to mediate a phagocytic signal. These results show that FcRIIB negatively regulates phagocytic signaling by FcRIIA and suggests that FcRIIB plays a role in modulating FcRIIA function in vivo.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1762-1768
© 1998 by The American Society of Hematology.
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