IL-17A both initiates (via IFNγ suppression) and limits the pulmonary type 2 immune response to nematode infection

Nippostrongylus brasiliensis is a well-defined model of type 2 immunity but the early lung-migrating phase is dominated by innate IL-17A production and neutrophilia. While the importance of IL-17A is well established during microbial infections, its contribution to type 2 immunity is poorly understood. Using N. brasiliensis infection we show that Il17a-KO mice exhibited an impaired type 2 immune response correlating with increased worm burden. Neutrophil depletion and reconstitution studies demonstrated that neutrophils contributed to the subsequent eosinophilia but were not responsible for the ability of IL-17A to promote type 2 cytokine responses. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased IFNγ signature in the Il17a-KO mice confirmed by enhanced IFNγ protein production. Depletion of early IFNγ restored type 2 immune responses in the Il17a-KO mice supporting the hypothesis that the suppression of IFNγ by innate IL-17A sources promotes the protective type 2 immune response. Notably, when IL-17A was blocked later in infection, there was an increased type 2 response. Combined data from both N. brasiliensis and Trichuris muris, a gut-specific pathogen, demonstrated that IL-17A regulation of type 2 immunity was lung-specific. Together our data suggest that IL-17A is a major regulator of type 2 immunity in the lung which supports the development of a protective type 2 immune response but subsequently limits the magnitude of that response.