Negative regulation of mast cell proliferation by FcγRIIB

• Published in: Molecular Immunology 2002-09, Vol.38 (16), p.1295-1299
• Main Authors: Malbec, Odile, Attal, Jean-Pierre, Fridman, Wolf H., Daëron, Marc
• Format: Article
• Language: English
• Subjects: Mast cell; Negative regulation; Proliferation
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/S0161-5890(02)00078-0

FcγRIIB are single-chain low-affinity receptors for the Fc portion of IgG antibodies that are widely expressed by hematopoietic cells including mast cells. We previously demonstrated that FcγRIIB negatively regulate cell activation triggered by receptors that possess Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) including high-affinity IgE receptors (FcεRI). FcγRIIB possess an Immunoreceptor Tyrosine-based Inhibition Motif (ITAM) whose deletion or mutation abolishes inhibition. When coaggregated with FcεRI, the FcγRIIB ITIM is tyrosyl-phosphorylated by the src family protein tyrosine kinase lyn, and recruits the SH2 domain-containing inositol 5-phosphatase SHIP that accounts for inhibition of cell activation. We found recently that, when coaggregated with Kit, FcγRIIB can also inhibit mast cell proliferation: thymidine incorporation is inhibited, cells do not enter the G1 phase of the cell cycle, the induction of cyclins D2, D3 and A is inhibited, the activation of the MAP kinases Erk1/2, JNK and p38 is decreased, Akt phosphorylation is inhibited, and SHIP coprecipitates with FcγRIIB. Although inhibition of Akt phosphorylation and Erk activation was abrogated in SHIP −/− cells, inhibition of thymidine incorporation was only partially reduced. FcγRIIB-dependent inhibition of Kit-mediated mast cell proliferation was however mimicked by FcγRIIB whose intracytoplasmic domain was replaced by the catalytic domain of SHIP. We also found that FcγRIIB can inhibit the proliferation of cells whose proliferation was rendered growth factor-independent because they express a mutated form of Kit that renders this RTK constitutively activated. Based on these results we developed models aiming at using FcγRIIB as targets for new therapeutic approaches of disease associated with mast cell activation such as allergies and diseases associated with mast cell proliferation such as mastocytosis, mastocytomas or mast cell leukemias.