Eosinophil-derived IFN-γ induces airway hyperresponsiveness and lung inflammation in the absence of lymphocytes

Background Eosinophils are key players in T H 2-driven pathologies, such as allergic lung inflammation. After IL-5– and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti–IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T H 2 lymphocytes at the inflammatory site. Objective The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated. Methods Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-γ–deficient BALB/c recipients. Results Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-γ expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-γ neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-γ–deficient eosinophils or eosinophils treated with a blocking anti–IFN-γ receptor antibody failed to induce AHR in IFN-γ–deficient recipients. Finally, in vitro and at low concentrations, IFN-γ increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism. Conclusions These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-γ, the prototypical T H 1 cytokine.