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Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity

Nature Immunology volume 12, pages 631–638 (2011)Cite this article

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Abstract

Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)–IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.

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Figure 1: H3N1 infection causes AHR and inflammation.
Figure 2: ST2-deficient mice fail to develop H3N1-induced AHR.
Figure 3: H3N1-induced AHR requires TLR7 and MyD88.
Figure 4: H3N1-induced production of IL-33 in alveolar macrophages.
Figure 5: H3N1 infection results in a greater abundance of natural helper cells in the lungs.
Figure 6: IL-13 and natural helper cells cause AHR.
Figure 7: Natural helper cells are essential for H3N1-induced AHR in Rag2−/− mice.

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Acknowledgements

We thank M. Grusby (Harvard School of Public Health) for CD1d-deficient mice (backcrossed to the BALB/c strain) and Z. Luo for technical support. Supported by the US National Institutes of Health (R01 AI068085, R01 HL62348 and R01 051354).

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Author notes

  1. Ya-Jen Chang and Hye Young Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Immunology and Allergy, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Ya-Jen Chang, Hye Young Kim, Lee A Albacker, Rosemarie H DeKruyff & Dale T Umetsu

  2. Center for Comparative Medicine, University of California, Davis, California, USA

    Nicole Baumgarth

  3. MRC Laboratory of Molecular Biology, Cambridge, UK

    Andrew N J McKenzie

  4. Department of Inflammation Research, Amgen, Seattle, Washington, USA.,

    Dirk E Smith

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Contributions

Y.-J.C. designed the study, did experiments, analyzed the data and wrote the manuscript; H.Y.K. did experiments and analyzed the data; L.A.A. did experiments; N.B. provided the H3N1 virus and did experiments. A.N.J.M., D.E.S. and R.H.D. provided reagents and ST2-deficient (Il1rl1−/−) and IL-13 deficient (Il13−/−) mice; and D.T.U. designed the study and wrote the manuscript.

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Correspondence to Dale T Umetsu.

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Competing interests

D.E.S. is an employee and shareholder of Amgen.

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Chang, YJ., Kim, H., Albacker, L. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12, 631–638 (2011). https://doi.org/10.1038/ni.2045

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