Structure/function relationships of Fc gamma receptors in phagocytosis.

An important function of Fc gamma 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 Fc gamma receptor isoforms. To examine this issue, an in-vitro model system in COS-1 cells has been developed. When transfected with an appropriate Fc gamma receptor, COS-1 cells which lack endogeneous Fc receptors, ingest IgG-sensitized cells. Using this model, a single class of human Fc gamma receptor in the absence of other Fc receptors was observed to mediate phagocytosis. Furthermore, isoforms from each Fc gamma 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 gamma chains. 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 Fc gamma receptor, Fc gamma RIIA. Fc gamma RI and Fc gamma RIIIA do not possess cytoplasmic tyrosines, but transmit a phagocytic signal through interaction with an associated gamma-subunit which contains two YXXL sequences in a conserved motif required for phagocytosis. The human Fc gamma RII isoforms, Fc gamma RIIB2, do not induce phagocytosis and have only a single YXXL sequence. Crosslinking of the phagocytic Fc gamma receptors induces tyrosine phosphorylation of either Fc gamma RIIA or the gamma 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 gamma chain in monocytes/macrophages, dramatically enhances phagocytosis mediated by Fc gamma RI and Fc gamma RIIIA and also induces non-phagocytic Fc gamma RI or Fc gamma RIIIA expressing cells to acquire phagocytic capability.