Natural killer cells regulate allergic lung inflammation by acting on group 2 innate lymphoid cells.

Abstract

Abstract In allergic asthma, inhalation of airborne allergens such as the house dust mite (HDM) effectively activates both innate and adaptive immunity in the lung. Endogenously generated cannabinoids and eicosanoids (acting via CB2 or PGI2-IP receptors, respectively) play important roles in both homeostatic and inflammatory processes including allergic airway inflammation. In this study, HDM responses in CB2 receptor–deficient (CB2−/−) or IP−/− mice were compared with wild type (WT) counterparts. Surprisingly, both CB2−/− and IP−/− mice had increased numbers of pulmonary natural killer cells (NK cells) producing IFN-γ that was inversely associated with the number of group 2 innate lymphoid cells (ILC2s) expressing IL-33Rα and IL-13 compared with WT animals. Remarkably, CB2−/− or IP−/− mice were less responsive to HDM challenge than WT counterparts since intranasal instillation of the allergen induced markedly reduced levels of airway eosinophils, CD4+ lymphocyte infiltration, and mucus production, as well as depressed levels of type 2 cytokines. NK cells and their production of IFN-γ were responsible for such attenuated inflammatory responses because depletion of NK cells or inhibition of IFN-γ production in vivo in CB2−/− or IP−/− mice restored both the HDM-induced allergic inflammation and ILC2 numbers in the lungs. Collectively, these data demonstrate a role for these eicosanoids in regulating the number and properties of NK cells resident in lung tissue and reveal a crucial role for NK cells in the regulation of lung tissue ILC2s and the development of allergic lung inflammatory responses.