[No authors listed]
Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcÉRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcÉRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcÉRI signals for DC function remain poorly understood. We show that humanized mice that express FcÉRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcÉRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FcÉRI-humanized DCs. Furthermore, conferring expression of FcÉRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcÉRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcÉRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcÉRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.
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