Article | Published:

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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1.

    & The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

  2. 2.

    , & Innate lymphoid cells in inflammation and immunity. Immunity 41, 366–374 (2014).

  3. 3.

    et al. Innate lymphoid cells--a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

  4. 4.

    et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).

  5. 5.

    et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J. Exp. Med. 211, 563–577 (2014).

  6. 6.

    et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).

  7. 7.

    et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).

  8. 8.

    et al. Critical role of p38 and GATA3 in natural helper cell function. J. Immunol. 191, 1818–1826 (2013).

  9. 9.

    et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13, 58–66 (2012).

  10. 10.

    , , & T-bet and Gata3 in controlling type 1 and type 2 immunity mediated by innate lymphoid cells. Curr. Opin. Immunol. 25, 139–147 (2013).

  11. 11.

    et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).

  12. 12.

    et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

  13. 13.

    et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75–82 (2009).

  14. 14.

    et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).

  15. 15.

    , , & Control of epithelial cell function by interleukin-22-producing RORγt+ innate lymphoid cells. Immunology 132, 453–465 (2011).

  16. 16.

    , & Development, differentiation, and diversity of innate lymphoid cells. Immunity 41, 354–365 (2014).

  17. 17.

    , & Expansion of human NK-22 cells with IL-7, IL-2, and IL-1β reveals intrinsic functional plasticity. Proc. Natl. Acad. Sci. USA 107, 10961–10966 (2010).

  18. 18.

    et al. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22. Blood 113, 4008–4010 (2009).

  19. 19.

    et al. Interleukin-1β selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 32, 803–814 (2010).

  20. 20.

    et al. A T-bet gradient controls the fate and function of CCR6RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).

  21. 21.

    et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).

  22. 22.

    et al. Distinct requirements for T-bet in gut innate lymphoid cells. J. Exp. Med. 209, 2331–2338 (2012).

  23. 23.

    et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).

  24. 24.

    et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).

  25. 25.

    & Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N. Engl. J. Med. 359, 2355–2365 (2008).

  26. 26.

    , , , & Exacerbation phenotyping in chronic obstructive pulmonary disease. Respirology 18, 1280–1281 (2013).

  27. 27.

    et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am. J. Respir. Crit. Care Med. 183, 734–742 (2011).

  28. 28.

    et al. Prevalence of viral infection detected by PCR and RT-PCR in patients with acute exacerbation of COPD: a systematic review. Respirology 15, 536–542 (2010).

  29. 29.

    et al. IL-1α/IL-1R1 expression in chronic obstructive pulmonary disease and mechanistic relevance to smoke-induced neutrophilia in mice. PLoS One 6, e28457 (2011).

  30. 30.

    et al. IL-18 is induced and IL-18 receptor α plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J. Immunol. 178, 1948–1959 (2007).

  31. 31.

    et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity 42, 566–579 (2015).

  32. 32.

    & Innate immunity to influenza virus infection. Nat. Rev. Immunol. 14, 315–328 (2014).

  33. 33.

    , & T-bet: a bridge between innate and adaptive immunity. Nat. Rev. Immunol. 13, 777–789 (2013).

  34. 34.

    et al. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40, 378–388 (2014).

  35. 35.

    et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).

  36. 36.

    et al. Genetic epidemiology of COPD (COPDGene) study design. COPD 7, 32–43 (2010).

  37. 37.

    et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat. Immunol. (25 April 2016).

  38. 38.

    et al. Gata3 drives development of RORγt+ group 3 innate lymphoid cells. J. Exp. Med. 211, 199–208 (2014).

  39. 39.

    et al. Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat. Immunol. 17, 169–178 (2016).

  40. 40.

    et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43, 354–368 (2015).

  41. 41.

    et al. Interleukin-1β, -4 and -12 control ILC2 fate in human airway inflammation. Nat. Immunol. (25 April 2016).

  42. 42.

    & IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722–728 (2012).

  43. 43.

    et al. Interleukin-33 and Interferon-γ counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity 43, 161–174 (2015).

  44. 44.

    et al. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat. Immunol. 17, 65–75 (2016).

  45. 45.

    et al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat. Immunol. 17, 76–86 (2016).

  46. 46.

    et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 3, e01659 (2014).

  47. 47.

    , & The influence of cigarette smoking on viral infections: translating bench science to impact COPD pathogenesis and acute exacerbations of COPD clinically. Chest 143, 196–206 (2013).

  48. 48.

    et al. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J. Clin. Invest. 123, 3967–3982 (2013).

  49. 49.

    et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

  50. 50.

    et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

  51. 51.

    et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).

  52. 52.

    et al. CD4+ T-Cell profiles and peripheral blood ex-vivo responses to T-cell directed stimulation delineate COPD phenotypes. J. COPD Found. 2, 268–280 (2016).

Download references

Acknowledgements

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

Affiliations

  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

Authors

  1. Search for Jonathan S Silver in:

  2. Search for Jennifer Kearley in:

  3. Search for Alan M Copenhaver in:

  4. Search for Caroline Sanden in:

  5. Search for Michiko Mori in:

  6. Search for Li Yu in:

  7. Search for Gretchen Harms Pritchard in:

  8. Search for Aaron A Berlin in:

  9. Search for Christopher A Hunter in:

  10. Search for Russell Bowler in:

  11. Search for Jonas S Erjefalt in:

  12. Search for Roland Kolbeck in:

  13. Search for Alison A Humbles in:

Contributions

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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Tables 1 and 2

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.3443

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing