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Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs

Nature Immunology volume 17, pages 626635 (2016) | Download Citation

  • An Erratum to this article was published on 19 July 2016

This article has been updated


Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.

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Change history

  • 05 May 2016

    In the version of this article initially published online, the units in the vertical axis for Figure 1l were incorrectly stated as '(fold)', and the figure lacked a key. The correct units are '(ng/ml; change from mock)'; the white bars are IL-5, the gray bars are IL-13, and the black bars are IFN-γ. Also, the lowest portions of the images in Figure 4i,j (including the inset in Figure 4j) were incorrectly cropped. The errors have been corrected for the print, PDF and HTML versions of this article.


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We thank the MedImmune Flow Cytometry core for all cell sorting; the MedImmune histology core for embedding tissues; the LAR staff for maintaining the experimental mice; M. Stämpfli for expertise and guidance in establishing a smoking system at MedImmune; A. Gonzales for running and maintaining the system for in-house exposure to cigarette smoke; the C. Lopez laboratory (University of Pennsylvania, School of Veterinary Medicine) for influenza virus strain PR8; M. Snaith for help with generating the ST2-GFP reporter mouse; M.E.P. Roberts for facilitating the collaboration with National Jewish Health; C. Schnell, T. Thorn and the rest of the team at NJH for commitment and contributions to this collaborative effort; and J. Jönsson and K. Jansner for histological work and image processing and analysis.

Author information


  1. Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.

    • Jonathan S Silver
    • , Jennifer Kearley
    • , Alan M Copenhaver
    • , Aaron A Berlin
    • , Roland Kolbeck
    •  & Alison A Humbles
  2. Department of Experimental Medical Science, Lund University, Lund, Sweden.

    • Caroline Sanden
    • , Michiko Mori
    •  & Jonas S Erjefalt
  3. Medetect, Lund, Sweden.

    • Caroline Sanden
    •  & Jonas S Erjefalt
  4. Non-Clinical Biostatistics, Department of Translational Sciences, MedImmune, Gaithersburg, Maryland, USA.

    • Li Yu
  5. University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.

    • Gretchen Harms Pritchard
    •  & Christopher A Hunter
  6. National Jewish Health, Denver, Colorado, USA.

    • Russell Bowler


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J.S.S., J.K. and A.A.H. planned all experiments; J.S.S. and J.K. executed and analyzed all experiments; A.M.C., L.Y., G.H.P. and A.A.B. planned and executed specific experiments; C.S., M.M. and J.S.E. cut, stained and analyzed all histology sections and developed the algorithms for analysis of ILC location; L.Y. analyzed and generated the statistical data and graphs for the COPDGene study; G.H.P. and C.A.H. provided Tbx21−/− mice and reagents; R.B. provided blood samples from patients with COPD and control subjects; C.A.H., J.S.E., R.K. and A.A.H. provided feedback and edits; and J.S.S. and A.A.H. wrote the manuscript.

Competing interests

J.S.S., J.K., A.M.C., L.Y., A.A.B., R.K. and A.A.H. are employed by and shareholders of MedImmune, and C.S., M.M., G.H.P., C.A.H., R.B. and J.S.E. have received funding from MedImmune.

Corresponding author

Correspondence to Alison A Humbles.

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