Regulation of mast cells’ secretory response by co‐clustering the Type 1 Fcϵ receptor with the mast cell function‐associated antigen

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The mast cell function-associated antigen (MAFA) is a type II membrane glycoprotein first identified on rat mast cells and basophils. Clustering MAFA inhibits these cells' secretory response to the type 1 Fcepsilon receptor (FcepsilonRI) stimulus. To quantitatively characterize this inhibition and its dependence on MAFA-FcepsilonRI co-clustering, we investigated the secretory response of rat mucosal-type mast cells of the RBL 2H3 line carrying an IgE class, 2,4 dinitrophenyl (DNP) specific monoclonal antibody to DNP-conjugated Fab and F(ab')(2) fragments of (1) mouse IgG, and (2) of the MAFA-specific, monoclonal antibody G63. The first reagent clusters FcepsilonRI-IgE complexes into oligomers by reacting with the DNP residues. The DNP conjugated G63 Fab and F(ab')(2) fragments, additionally aggregate MAFA and form FcepsilonRI-IgE-MAFA co-clusters. All experiments using these ligands were performed in the absence or presence of an excess of intact mAb G63, which clusters MAFA molecules. Empirical Hill functions were used to relate the secretory response of mast cells to the equilibrium concentrations of FcepsilonRI-IgE or MAFA clusters and co-clusters calculated as function of the employed ligands concentrations. This analysis of the experimental results indicates that co-clustered MAFA molecules have a markedly higher inhibitory capacity than MAFA-clusters alone. The molecular basis of the enhanced inhibition observed upon co-clustering MAFA with the FcepsilonRI is most probably the increased concentration of the inhibitory cell components in the immediate proximity of the activation coupling elements.