MOUSE MAST-CELL GP49B1 CONTAINS 2 IMMUNORECEPTOR TYROSINE-BASED INHIBITION MOTIFS AND SUPPRESSES MAST-CELL ACTIVATION WHEN COLIGATED WITH THE HIGH-AFFINITY FC RECEPTOR FOR IGE

Mouse mast cells express gp49B1, a cell-surface member of the Ig super family encoded by the gp49B gene, We now report that by ALIGN comparis on of the amino acid sequence of gp49B1 with numerous receptors of the Ig superfamily, a newly recognized family has been established that i ncludes gp49B1, the human myeloid cell Fc receptor for IgA, the bovine myeloid cell Fc receptor for IgG2, and the human killer cell inhibito ry receptors expressed on natural killer cells and T lymphocyte subset s, Furthermore, the cytoplasmic domain of gp49B1 contains two immunore ceptor tyrosine-based inhibition motifs that are also present in kille r cell inhibitory receptors; these motifs downregulate natural killer cell and T-cell activation signals that lead to cytotoxic activity, As assessed by flow cytometry with transfectants that express either gp4 9B1 or gp49A, which are 89% identical in the amino acid sequences of t heir extracellular domains, mAb B23.1 was shown to recognize only gp49 B1, Coligation of mAb B23.1 bound to gp49B1 and IgE fixed to the high- affinity Fc receptor for IgE on the surface of mouse bone marrow-deriv ed mast cells inhibited exocytosis in a dose-related manner, as define d by the release of the secretory granule constituent beta-hexosaminid ase, as well as the generation of the membrane-derived lipid mediator, leukotriene C-4. Thus, gp49B1 is an immunoreceptor tyrosine-based inh ibition motif-containing integral cell-surface protein that downregula tes the high-affinity Fc receptor for IgE-mediated release of proinfla mmatory mediators from mast cells, Our findings establish a novel coun terregulatory transmembrane pathway by which mast cell activation can be inhibited.