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

ABSTRACTNippostrongylus brasiliensisis a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production and neutrophilia. UsingN. brasiliensisinfection we confirm previous observations thatIl17a-KO mice exhibit an impaired type-2 immune response. Neutrophil depletion and reconstitution studies demonstrated that neutrophils contribute to the subsequent eosinophilia but are not responsible for the ability of IL-17A to promote type-2 cytokine responses. Transcriptional profiling of the lung on day 2 ofN. brasiliensisinfection revealed an increasedIfnγsignature in theIl17a-KO mice confirmed by enhanced IFNγ protein production. Depletion of early IFNγ rescued type-2 immune responses in theIl17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, when IL-17A was blocked later in infection, the type-2 response increased. IL-17A regulation of type-2 immunity was lung-specific and infection withTrichuris muris,revealed that IL-17A promotes a type-2 immune response in the lung even when a parasite lifecycle is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity which supports the development of a protective type-2 immune response but subsequently limits the magnitude of that response.