Regulation of mast cell activation through FcεRI

The cross-linking of FcεRI on mast cells by IgE and antigen (Ag) initiates activation cascades that lead to allergic responses. FcεRI is composed of an α and a β monomer, and a γ homodimer, and the β and γ chains possess immunoreceptor tyrosine-based activation motifs (ITAMs). Through the phosphorylation of ITAMs, activation signals are transmitted intracellularly. Mast cells are also activated through FcγR-FcRγ by an immune complex, which often results in hypersensitivity. We defined FcRγ-signal-dependent and -independent mast cell responses by analyzing FcRγ^-/- mice reconstituted with mutant FcRγ-ITAM. Most of the FcεRI-mediated activations by IgE(+Ag), such as induction of degranulation, arachidonic acid metabolism, cytokine production and systemic anaphylaxis, are dependent on signaling through FcRγ-ITAM. On the other hand, IgE without Ag induces the upregulation of surface FcεRI expression and mast cell survival. The former is independent of and the latter is dependent on FcRγ-ITAM. As a molecular mechanism for the generation of diverse responses through FcεRI, we found that the quantity and the duration of the FcRγ signal determine the degranulation and the survival of mast cells, respectively. Furthermore, such a sustained FcRγ-signal-induced survival is mediated by autocrine cytokine production. In this review, the in vivo function of FcRγ and the signal regulation for the distinct responses of mast cells through FcεRI are discussed.