IL-17A both initiates, via IFN\u03b3 suppression, and limits the pulmonary type-2 immune response to nematode infection

Jesuthas Ajendra,Brian H K Chan,Louis Boon,Stefano A P Colombo,Alistair L Chenery,Judith E Allen,Richard K Grencis,Tara E Sutherland,Stella Pearson,James E Parkinson

doi:10.1038/s41385-020-0318-2

Abstract

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.

Highlights

Innate and adaptive sources of interleukin-17A (IL-17A) are responsible for a range of neutrophil-associated inflammatory conditions as well as protection from many bacterial and fungal pathogens.[1,2] In contrast, type-2 immunity is required for effective control of most helminth infections[3] and is characterized by eosinophilic inflammation and the cytokines IL-4, IL-5 and IL-13
We found that IL-17A suppressed early IFNγ production and that this suppression was essential for the optimal development of a type-2 response
IL-17A-deficient mice mount a diminished type-2 response In keeping with the known ability of N. brasiliensis to induce a strong pulmonary type-2 immune response on day 6 post infection (d6pi), we found the bronchoalveolar lavage (BAL) and lungs of C57BL/6 mice to be dominated by eosinophils (Supplementary Fig. 1a, b)

Summary

Introduction

Innate and adaptive sources of interleukin-17A (IL-17A) are responsible for a range of neutrophil-associated inflammatory conditions as well as protection from many bacterial and fungal pathogens.[1,2] In contrast, type-2 immunity is required for effective control of most helminth infections[3] and is characterized by eosinophilic inflammation and the cytokines IL-4, IL-5 and IL-13. Type-2 cytokines can actively suppress IL-17A production which may be an important feedback mechanism to avoid extreme IL-17Adriven pathology.[8,9,10] Despite evidence for an important relationship between IL-17A and type-2 immune responses during chronic disease, how these responses are connected remain poorly understood

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Conclusion