Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity

摘要

Background: IL-4, IL-5, and IL-13 are thought to be central to the allergic asthmatic response. Previous work supposed that the essential source of these cytokines was CD4 + T H2 cells. However, more recent studies have suggested that other innate production of type 2 cytokines might be as important. Objectives: Nuocytes are a novel population of IL-13-producing innate cells, which are critical for protective immunity in Nippostrongylus brasiliensis infection. Given this, we investigated the potential existence and functional importance of nuocytes in experimental allergic asthma. Methods: We generated Il4 +/eGFPIl13 +/Tomato dual-reporter mice to study cytokine-producing cells during allergic inflammation. We adoptively transferred innate IL-13-producing cells to investigate their role in airways hyperreactivity (AHR). Results: We show that allergen-induced nuocytes infiltrate the lung and are a major innate source of IL-13. CD4 + T cells in the lung almost exclusively express only IL-13, whereas IL-4-producing T cells were restricted to the draining lymph nodes. Intranasal administration of IL-25 or IL-33 induced IL-13-producing nuocytes in the BAL fluid. Strikingly, adoptive transfer of wild-type nuocytes, but not Il13 -/- nuocytes, into Il13 -/- mice, which are normally resistant to IL-25-induced AHR, restored airways resistance and lung cell infiltration. Conclusions: These findings identify nuocytes as a novel cell type in allergic lung inflammation and an innate source of IL-13 that can directly induce AHR in the absence of IL-13-producing CD4 + T cells. These data highlight nuocytes as an important new consideration in the development of future allergic asthma therapy.