IgEb immune complexes activate macrophages through FcγRIV binding

Abstract

Because functional analysis of Fc receptors (FcRs) relies heavily on mouse models, the identification of another Fcγ receptor is particularly noteworthy. We demonstrate that FcγRIV, identified here as the mouse ortholog of primate FcγRIII, required association of the FcR γ-chain for optimal expression and function on myeloid cells; its signaling potential was also enhanced by a cytoplasmic 'YEEP' motif that was able to recruit the adaptor molecule Crk-L and phosphatidylinositol-3-OH kinase. Unexpectedly, FcγRIV 'preferentially' bound immunoglobulin E antibodies of the 'b' allotype (IgE^b) as well as IgG2a and IgG2b antibodies. Ligation of FcγRIV by antigen-IgE^b immune complexes promoted macrophage-mediated phagocytosis, presentation of antigen to T cells, production of proinflammatory cytokines and the late phase of cutaneous allergic reactions. IgE^b antibody–mediated modification of macrophage responses may therefore influence mouse asthma models and strain-dependent differences in parasite susceptibility.