Abstract

Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor α-chain (CD25), IL-7 receptor α-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.

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Acknowledgements

We thank all members of the Artis and Wherry laboratories; M. Siracusa, S. Saenz, L. Osborne, E. Tait Wojno, M. Noti, M. Nair and A. Crawford for discussions and critical reading of the manuscript; D. Kobuley and D. Hill for care of the germ-free mouse facility; Yadav and A. Fitzgerald for assistance with the human BAL samples; and L. Fouser, S. Olland, R. Zollner, K. Lam and A. Root (Pfizer) for the preparation of anti-IL-22. Supported by US National Institutes of Health (U19AI083022, AI071309 and HHSN266200500030C to E.J.W.; HL098957 to R.G.C. for human pulmonary BAL studies; AI061570, AI074878, AI087990, AI095608, AI091759, AI095466 and U01AI095608 to D.A.; T32AI007532 to L.A.M. and G.F.S.; and T32AI05528 to M.C.A.), the Burroughs Wellcome Fund (D.A.), the National Institute of Diabetes and Digestive and Kidney Diseases Center for the Molecular Studies in Digestive and Liver Diseases Molecular Pathology and Imaging Core (DK50306) and the University of Pennsylvania (D.A.).

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Affiliations

  1. Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Laurel A Monticelli
    • , Gregory F Sonnenberg
    • , Michael C Abt
    • , Theresa Alenghat
    • , Carly G K Ziegler
    • , Travis A Doering
    • , Jill M Angelosanto
    • , Brian J Laidlaw
    • , E John Wherry
    •  & David Artis
  2. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Laurel A Monticelli
    • , Gregory F Sonnenberg
    • , Michael C Abt
    • , Theresa Alenghat
    •  & David Artis
  3. Department of Biology, University of California San Diego, La Jolla, California, USA.

    • Cliff Y Yang
    •  & Ananda W Goldrath
  4. Department of Surgery and the Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA.

    • Taheri Sathaliyawala
    • , Masaru Kubota
    • , Damian Turner
    •  & Donna L Farber
  5. Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Joshua M Diamond
    •  & Ronald G Collman

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Contributions

L.A.M., G.F.S. and M.C.A. did experiments and analyzed data; T.A. analyzed lung histological specimens; C.G.K.Z. and T.A.D. did microarray analysis; J.M.A. and B.J.L. designed the method for quantifying influenza virus by quantitative RT-PCR; C.Y.Y. and A.W.G. generated and provided Id2-deficient fetal liver chimeras; T.S., M.K., D.T. and D.L.F. collected and processed human lung tissues; J.M.D. and R.G.C. collected and processed human BAL fluid; and L.A.M., E.J.W. and D.A. designed the study, analyzed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to E John Wherry or David Artis.

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DOI

https://doi.org/10.1038/ni.2131

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