Insights into immunoglobulin E receptor signaling from structurally defined ligands

Summary:  The asymmetrical structure of bent immunoglobulin E (IgE) bound to its high‐affinity receptor, FcɛRI, suggests a possible role for this configuration in the regulation of signaling mediated by cross‐linking of FcɛRI on the surface of mast cells and basophils. Indeed, the presence of bound IgE strongly influences the capacity of cross‐linked FcɛRI dimers to trigger mast cell degranulation, implicating orientational constraints by bound IgE. Bivalent ligands that cross‐link by binding to bivalent IgE can form linear and cyclic chains of IgE/FcɛRI complexes, and these exhibit only limited capacity to stimulate downstream signaling and degranulation, whereas structurally analogous trivalent ligands, which can form branched networks of cross‐linked IgE/FcɛRI complexes, are more effective at cell activation. Long bivalent ligands with flexible spacers can form intramolecular cross‐links with IgE, and these stable 1:1 complexes are very potent inhibitors of mast cell degranulation stimulated by multivalent antigen. In contrast, trivalent ligands with rigid double‐stranded DNA spacers effectively stimulate degranulation responses in a length‐dependent manner, providing direct evidence for receptor transphosphorylation as a key step in the mechanism of signaling by FcɛRI. Thus, studies with chemically defined oligovalent ligands show important features of IgE receptor cross‐linking that regulate signaling, leading to mast cell activation.