Structure/function relationships of Fcγ receptors in phagocytosis

Abstract

An important function of Fcγ receptors is the ingestion or phagocytosis of IgG sensitized cells. It has been difficult to clearly define the individual function of each receptor in phagocytosis because hematopoietic cells express multiple Fcγ receptor isoforms. To examine this issue, an in-vitro model system in COS-1 cells has been developed. When transfected with an appropriate Fcγ receptor, COS-1 cells which lack endogeneous Fc receptors, ingest IgG-sensitized cells. Using this model, a single class of human Fcγ receptor in the absence of other Fc receptors was observed to mediate phagocytosis. Furthermore, isoforms from each Fcγ receptor class can mediate phagocytosis although the requirements for phagocytosis differ. Investigation of the relationship between structure and function for Fc receptor-mediated phagocytosis established the importance of the cytoplasmic tyrosines of the receptor or its associated γ chain. For example, two cytoplasmic YXXL sequences, in a configuration similar to the conserved tyrosine containing motif found in immunoglobulin gene family receptors, are important for phagocytosis by the human Fcγ receptor, Fcγ RIIA. Fcγ RI and Fcγ RIIIA do not possess cytoplasmic tyrosines, but transmit a phagocytic signal through interaction with an associated γ-subunit which contains two YXXL sequences in a conserved motif required for phagocytosis. The human Fcγ RII isoforms, Fcγ RIIB1 and Fcγ RIIB2, do not induce phagocytosis and have only a single YXXL sequence. Crosslinking of the phagocytic Fcγ receptors induces tyrosine phosphorylation of either Fcγ RIIA or the γ chain and treatment with tyrosine kinase inhibitors reduces both phagocytosis and phosphorylation of the receptor tyrosine residues. The protein tyrosine kinase Syk, which is associated with the γ chain in monocytes/macrophages, dramatically enhances phagocytosis mediated by Fcγ RI and Fcγ RIIIA and also induces non-phagocytic Fcγ RI or Fcγ RIIIA expressing cells to acquire phagocytic capability.