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IL-15 Promotes Polyfunctional NK Cell Responses to Influenza by Boosting IL-12 Production.

  • Wagstaffe, Helen R1
  • Nielsen, Carolyn M1, 2
  • Riley, Eleanor M1, 3
  • Goodier, Martin R4
  • 1 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom. , (United Kingdom)
  • 2 Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom; and. , (United Kingdom)
  • 3 The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom. , (United Kingdom)
  • 4 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom; [email protected] , (United Kingdom)
Published Article
The Journal of Immunology
The American Association of Immunologists
Publication Date
Feb 28, 2018
DOI: 10.4049/jimmunol.1701614
PMID: 29491009


IL-15 is a key regulator of NK cell maintenance and proliferation and synergizes with other myeloid cell-derived cytokines to enhance NK cell effector function. At low concentrations, trans-presentation of IL-15 by dendritic cells can activate NK cells, whereas at higher concentrations it can act directly on NK cells, independently of accessory cells. In this study, we investigate the potential for IL-15 to boost responses to influenza virus by promoting accessory cell function. We find that coculture of human PBMCs with inactivated whole influenza virus (A/Victoria/361/2011) in the presence of very low concentrations of IL-15 results in increased production of myeloid cell-derived cytokines, including IL-12, IFN-α2, GM-CSF, and IL-1β, and an increased frequency of polyfunctional NK cells (defined by the expression of two or more of CD107a, IFN-γ, and CD25). Neutralization experiments demonstrate that IL-15-mediated enhancement of NK cell responses is primarily dependent on IL-12 and partially dependent on IFN-αβR1 signaling. Critically, IL-15 boosted the production of IL-12 in influenza-stimulated blood myeloid dendritic cells. IL-15 costimulation also restored the ability of less-differentiated NK cells from human CMV-seropositive individuals to respond to influenza virus. These data suggest that very low concentrations of IL-15 play an important role in boosting accessory cell function to support NK cell effector functions.

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