LAUSR

Exclusion of a phosphatase from regions of antigen-receptor engagement facilitates mast cell activation. Mast cells get exclusive The mast cell receptor FcεRI binds to antibody-bound antigens and then activates and recruits cytosolic kinases to stimulate allergic responses. Although receptor aggregation by multivalent antigens is a well-characterized mechanism of FcεRI activation, the receptor also responds to monovalent antigens. Felce et al. used imaging and functional analyses to show that the exclusion of a phosphatase from regions of the plasma membrane in which FcεRI was engaged by surface-bound, monovalent antigens led to receptor-induced kinase activity and mast cell stimulation. This form of receptor triggering may be combined with antigen-induced receptor aggregation-based signaling to extend the reactivity of mast cells to antigens. For many years, the high-affinity receptor for immunoglobulin E (IgE) FcεRI, which is expressed by mast cells and basophils, has been widely held to be the exemplar of cross-linking (that is, aggregation dependent) signaling receptors. We found, however, that FcεRI signaling could occur in the presence or absence of receptor cross-linking. Using both cell and cell-free systems, we showed that FcεRI signaling was stimulated by surface-associated monovalent ligands through the passive, size-dependent exclusion of the receptor-type tyrosine phosphatase CD45 from plasma membrane regions of FcεRI-ligand engagement. Similarly to the T cell receptor, FcεRI signaling could also be initiated in a ligand-independent manner. These data suggest that a simple mechanism of CD45 exclusion–based receptor triggering could function together with cross-linking–based FcεRI signaling, broadening mast cell and basophil reactivity by enabling these cells to respond to both multivalent and surface-presented monovalent antigens. These findings also strengthen the case that a size-dependent, phosphatase exclusion–based receptor triggering mechanism might serve generally to facilitate signaling by noncatalytic immune receptors.