Negative regulation of FcepsilonRI-mediated basophil activation by the Cbl family of adaptor proteins.

Basophils and mast cells have long been recognized as critical effector cells in IgE-mediated immune responses. Antigen interaction with specific IgE bound to the high-affinity Fc receptor for IgE, constitutively expressed on the cell-surface of basophils, generates signals that cause a shift in the resting state equilibrium of phosphorylation and dephosphorylation events that serves to maintain homeostasis. The outcome of this activated state is the release of a wide array of pro-inflammatory mediators. During the past few years, the existence of a negative feedback loop initiated upon FcεRI engagement has also been envisaged. This negative signal involves the coordinated action of adaptors, phosphatases and ubiquitin ligases that limits the intensity and duration of positive signals, thus modulating basophil functions. Relevant to this, others and we have demonstrated that Cbl proteins control the amplitude of FcεRI-generated signals mainly by specific ubiquitin modification of activated receptor subunits and associated protein tyrosine kinases. The identification of molecular mechanisms involved in basophil regulation, may provide new insights into how these cells can be manipulated to achieve therapeutic ends in the treatment of allergic disease.