Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology

Interleukin-25 (IL-25) is released from lung epithelial cells in response to allergen challenge and promotes type 2 immune responses and allergic airway inflammation. Nicholas Lukacs and his colleagues now report that IL-25 acts on a myeloid population in the lung. These cells represent a major source of IL-4 and IL-13, promote allergic lung inflammation and are steroid resistant. The frequency of IL-4– and IL-13–producing myeloid cells is increased in individuals with asthma, suggesting these cells may have a crucial role in the development of asthma. Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb−/− mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4+ T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell–independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25–mediated responses in Il17rb−/− mice. High-dose dexamethasone treatment did not reduce the IL-25–induced T2M pulmonary response. Finally, a similar IL-4– and IL-13–producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population.