Regulation of mast cell activation through FcepsilonRI

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