IL-17A+ group 2 innate lymphoid cells elicit mixed airway inflammation in chronic obstructive pulmonary disease

RationalePulmonary innate immune cells play a central role in the initiation and perpetuation of chronic obstructive pulmonary disease (COPD), however the precise mechanisms that orchestrate the development and severity of COPD are poorly understood. ObjectivesWe hypothesized that the recently described family of innate lymphoid cells (ILCs) play an important role in COPD. MethodsSubjects with COPD and healthy controls were clinically evaluated, and their sputum samples were assessed by flow cytometry. A mouse model of spontaneous COPD [genetically deficient in surfactant protein-D (SP-D-/-)] and ozone (O3) exposure were used to examine the mechanism by which lack of functional SP-D may skew ILC2s to produce IL-17A in combination with IL-5 and IL-13, leading to a mixed inflammatory profile and more severe disease. Measurements and Main ResultsCOPD was characterized by poor spirometry, sputum inflammation, and the emergence of sputum GATA3+ ILCs (ILC2s), but not T-bet+ ILCs (ILC1s) nor ROR{gamma}t+ ILCs (ILC3s). COPD subjects with elevated sputum ILC2s (the ILC2high group) had worse spirometry and sputum neutrophilia and eosinophilia than healthy and ILC2low subjects. This was associated with the presence of dual-positive IL-5+IL-17A+ and IL-13+IL-17A+ ILCs and nonfunctional SP-D in the sputum in ILC2high subjects. SP-D-/- mice showed spontaneous airway neutrophilia. Lack of SP-D in the mouse lung licensed ILC2s to produce IL-17A, which was dose-dependently inhibited by recombinant SP-D. SP-D-/- mice showed enhanced susceptibility to O3-induced airway neutrophilia, which was associated with the emergence of inflammatory IL-13+IL-17A+ ILCs. ConclusionsWe report that the presence of sputum ILC2s predicts the severity of COPD, and unravel a novel pathway of IL-17A plasticity in lung ILC2s, prevented by the immunomodulatory protein SP-D.