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A critical function for CD200 in lung immune homeostasis and the severity of influenza infection

Nature Immunology volume 9, pages 1074–1083 (2008)Cite this article

Abstract

The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.

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Figure 1: Expression of CD200 and CD200R expression in homeostasis.
Figure 2: Heightened responsiveness of Cd200−/− alveolar macrophages stimulated ex vivo.
Figure 3: Changes in CD200 and CD200R expression during influenza infection.
Figure 4: Enhanced inflammation in Cd200−/− mice infected with influenza.
Figure 5: Heightened myeloid and T cell responses in influenza-infected Cd200−/− mice.
Figure 6: CD200R signaling ameliorates influenza-induced inflammation.

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Acknowledgements

Influenza X31 virus was a gift from A. Douglas (National Institute for Medical Research, London); rat agonistic anti-mouse CD200R IgG1 was donated by N. Barclay (Oxford); and LA-4 cells were a gift from S. Johnston (Imperial College, London). Supported by the Medical Research Council (P171/03/C1/048), the US National Institutes of Health (NGA:1 U01 AI070232–01), the Wellcome Trust (082727/Z/07/Z) and the European Union (032296).

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Authors and Affiliations

  1. Imperial College London, Kennedy Institute, London, W6 8LH, UK

    Robert J Snelgrove, John Goulding, Arnaud M Didierlaurent, Daphne Lyonga, Seema Vekaria, Lorna Edwards, Emily Gwyer & Tracy Hussell

  2. Eli Lilly, Indianapolis, 46285, USA

    Jonathon D Sedgwick

  3. Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK

    A Neil Barclay

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  1. Robert J Snelgrove
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Contributions

T.H. and R.J.S. planned, executed and interpreted the experiments and prepared the manuscript; J.G. did many experiments and finalized the figures for publication; A.M.D. assisted with the purification of airway epithelial cells and alveolar macrophages; D.L., S.V., L.E. and E.G. provided technical contributions to the paper; and J.D.S. and A.N.B. provided key reagents and contributed discussions throughout the work.

Corresponding author

Correspondence to Tracy Hussell.

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Competing interests

T.H. has stock in and is assisting StormBio to develop an H5N1 mouse model to be used for testing cytokine blockade; CD200 may be considered if appropriate. J.D.S. is employed by and has stock in Eli Lilly.

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Snelgrove, R., Goulding, J., Didierlaurent, A. et al. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol 9, 1074–1083 (2008). https://doi.org/10.1038/ni.1637

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