Cell surface receptors for IgG (Fc gamma receptors) play a major role in immune defense mechanisms, since they form a bridge between the humoral immunity system and the effector cells, such as cells of the monocyte/macrophage lineage and myeloid elements. This proposal stems from the recent cloning of genes for murine Fc gamma receptors. We now appreciate that the macrophage and lymphocyte Fc gamma receptors, although they both react with monoclonal antibody 2.4G2, are quite different proteins, with closely conserved N-terminal domains and different transmembrane and cytoplasmic domains. The receptors, furthermore, are members of the immunoglobulin superfamily, sharing extensive homology with class II histocompatibility determinants. We would now like to analyze the structure/function relationships of these receptors in detail. It is possible to express the genes in non-lymphoid cells, and these transfected cells will be used to analyze the specificity of the receptor on a """"""""clean"""""""" background. A series of mutant receptors will be made and analyzed. Polyclonal and monoclonal antibodies against various domains of the receptor including the cytoplasmic domain and specific sites where there are differences in the N-terminal sequence. The antibodies will be used to probe function of the various domains. Transfected cells, and the various antibodies will be used in patch clamping studies. We will look for cytoplasmic or membrane antibodies that interact with cytoplasmic domains by various methods. Human Fc receptors isolated from various cell types by affinity chromatography with monoclonal antibody 3G8 will be analyzed for polymorphism. Human receptors will be cloned by cross- hybridization with the murine probes, or by sequence determination of human receptor followed by synthesis of oligonucleotide probes. Finally, the relationship between Mls and Fc gamma receptor will be investigated.
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