CD4+ T cell-specific deletion of IL-4 receptor α prevents ovalbumin-induced anaphylaxis by an IFN-γ-dependent mechanism

IL-4R alpha-mediated STAT6 activation serves an essential role in various animal models of allergy and asthma at both the. sensitization and effector phases. IL-4 and IL-13 signaling via the IL-4R alpha chain exacerbates murine anaphylaxis, but the cell-specific requirements for IL-4Ra expression are unclear. The purpose of this study was to elucidate the mechanisms of systemic anaphylaxis to OVA in gene-targeted mice with a deletion of the IL-4R alpha chain in the macrophage/neutrophil or CD4(+) T lymphocyte population. Results demonstrated that anaphylaxis in this model was entirely dependent upon the Fc gamma RII/III and was associated with mast cell degranulation. Expression of the IL-4R alpha on CD4(+) T cells, but not macrophages or neutrophils, was critical for severe anaphylaxis, characterized by diarrhea, hypothermia, and death. Ab depletion experiments demonstrated that IFN-gamma protected against mortality and severe intestinal pathology despite the presence of Ag and specific Ab. This protection was associated with reduced levels of mast cell protease, a marker of mast cell degranulation, suggesting that IFN-gamma may inhibit mast cell degranulation in vivo. These data suggest that it may be possible to limit the severity of anaphylaxis using rational therapies designed to increase numbers of IFN-gamma-producing cells by targeting IL-4R alpha signaling in CD4(+) T lymphocytes.