Receptors for antibody molecules of the IgG class (FcgammaR) on effector cells couple the humoral and cellular arms of the immune response by transducing signals to cells which result in phagocytosis, release of inflammatory mediators, antibody-dependent cellular cytotoxicity (ADCC) and immunomodulation. This functional heterogeneity has recently been addressed by the cloning and characterization of cDNAs isolated from mouse macrophage and lymphocyte cell lines which illustrate the structural diversity of this receptor family. Diversity is encoded in multiple genes from which alternatively spliced transcripts can arise, thereby coupling nearly identical extracellular domains which bind ligand to diverse transmembrane and intracytoplasmic domains. The functional contribution of each of these domains to these diverse cellular responses is being addressed by the transfection and expression of FcgammaR genes and chimeric rearrangements of these genes into FcgammaR- cell lines and determining the role of different protein domains to ligand binding, ion channel formation, phagocytosis and TH cell proliferation mediated by the Mls locus. Regulation of tissue specific expression of these genes in macrophage and lymphoid cells will be approached by the cloning and characterization of the genomic copies of these genes and the mapping of cis-acting sequences necessary for their expression. The structural and functional heterogeneity of the human FcgammaR system is accessible through use of the cloned mouse gene probes and has indicated the presence of multiple genes and transcripts. The molecular basis for human FcgammaR heterogeneity will be explored through the analysis of cDNA clones isolated from myeloid and lymphoid libraries and their expression by transfection into FcgammaR-cell lines. Expression of human FcgammaR genes in mouse macrophage lines (P388D1) will directly address their roles in phagocytosis and ADCC. In vitro mutational analysis of these genes will then address the role of different FcgammaR receptors in these effector functions. Structural analysis of these human FcgammaR genes will focus on their modulation during induced differentiation of the HL-60 cell line. The availability of both human and mouse FcgammaR homologues will allow for the construction of mouse-human hybrid molecules which will be used to probe the functional consequences of cross-linking FcgammaRs on macrophages and for the identification of conserved sequences which can then be evaluated for their role in the function and regulation of these molecules.
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