Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection

PLoS Pathog. 2013 Sep;9(9):e1003615. doi: 10.1371/journal.ppat.1003615. Epub 2013 Sep 19.

Abstract

Respiratory virus infections, such as influenza, typically induce a robust type I (pro-inflammatory cytokine) immune response, however, the production of type 2 cytokines has been observed. Type 2 cytokine production during respiratory virus infection is linked to asthma exacerbation; however, type 2 cytokines may also be tissue protective. Interleukin (IL)-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils into the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL-5 was group 2 innate lymphoid cells (ILC2) infiltrating the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance is reflected in the rapid expansion of c-kit⁺ IL-5 producing ILC2. We further demonstrate that the enhanced capacity for IL-5 production by ILC2 during recovery is concomitant with the enhanced expression of the IL-33 receptor subunit, ST2, by ILC2. Lastly, we show that NKT cells, as well as alveolar macrophages (AM), are endogenous sources of IL-33 that enhance IL-5 production from ILC2. Collectively, these results reveal that c-kit⁺ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and accounts for the accumulation of eosinophils observed during the recovery phase of influenza infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Eosinophilia / etiology
  • Eosinophils / immunology
  • Eosinophils / metabolism
  • Eosinophils / pathology
  • Eosinophils / virology
  • Immunity, Innate
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Interleukin-33
  • Interleukin-5 / metabolism*
  • Interleukins / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Killer Cells, Natural / virology
  • Lung / immunology*
  • Lung / metabolism
  • Lung / pathology
  • Lung / virology
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / metabolism
  • Macrophages, Alveolar / pathology
  • Macrophages, Alveolar / virology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Protein Subunits / metabolism
  • Receptors, Interleukin / metabolism
  • Respiratory Tract Infections / immunology*
  • Respiratory Tract Infections / metabolism
  • Respiratory Tract Infections / pathology
  • Respiratory Tract Infections / virology
  • Specific Pathogen-Free Organisms
  • Up-Regulation

Substances

  • Il33 protein, mouse
  • Interleukin-33
  • Interleukin-5
  • Interleukins
  • Protein Subunits
  • Receptors, Interleukin