CD45 exclusion– and cross-linking–based receptor signaling together broaden FcεRI reactivity

For many years, the high-affinity receptor for immunoglobulin E (IgE) FceRI, 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 FceRI signaling could occur in the presence or absence of receptor cross-linking. Using both cell and cell-free systems, we showed that FceRI 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 FceRI-ligand engagement. Similarly to the T cell receptor, FceRI 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 FceRI 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.