Activating and inhibitory signaling in mast cells: new opportunities for therapeutic intervention?

Immune responses are tightly controlled by the activities of both activating and inhibitory signals. At the cellular level, these signals are generated through engagement of membrane-associated receptors and coreceptors. The high-affinity IgE receptor FcepsilonRI is expressed on mast cells and basophils and, on cross-linking by multivalent antigen (allergen), stimulates the release of inflammatory mediators that induce acute allergic responses. Activation signals mediated by a variety of immune receptors (eg, B-cell receptor, T-cell receptor, and FcepsilonRI) are subject to negative regulation by a growing family of structurally and functionally related inhibitory receptors. Recent studies indicate that mast cells express multiple inhibitory receptors that may regulate FcepsilonRI-induced mast cell activation through similar mechanisms. The ability of inhibitory receptors to attenuate IgE-mediated allergic responses implicates them as potential targets for therapeutic intervention in the treatment of atopic disease. Indeed, coaggregation of activating and inhibitory receptors has been suggested as one possible mechanism to explain the beneficial effects of specific immunotherapy in the treatment of allergy. In this review we summarize the current knowledge of inhibitory receptors expressed in mast cells and the mechanisms through which they regulate mast cell function.