Abstract
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.
Highlights
Increased responses to inactivated whole influenza virus (H3N2) in the presence of IL-15 were reflected in increased mean fluorescence intensities (MFIs) for all NK cell functional markers at their optimal time points
A small, but significant, increase was observed in CD107a MFI at 6 h (H3N2 median 747 units, interquartile range [IQR] 718–776; H3N2+IL-15 median 768 units, IQR 735–813, p # 0.0001), IFN-g MFI increased substantially by 9 h (H3N2 median 681 units, IQR 523–814; H3N2+IL-15 median 1037 units, IQR 864–1179, p # 0.0001), and a significant shift in CD25 MFI was observed by 18 h (H3N2 median 72.5 units, IQR 34.7–153.8; H3N2+IL-15 median 371.5 units, IQR 249–508, p # 0.0001)
Many studies of the effect of IL-15 on NK cell activation focus on IL-15 trans-presentation or direct activation of NK cells with high concentrations of IL-15 in combination with other cytokines [5, 10]
Summary
To determine the effect of a low concentration of exogenous IL-15 on the frequency and kinetics of NK cell responses to influenza, IFN-g, CD107a, and CD25 were measured at 6, 9, and 18 h after stimulation of human PBMCs with H3N2 in the presence or absence of 0.75 ng/ml recombinant human IL-15. These data suggest that IL-15 potentiates NK cell responses to H3N2 by enhancing maturation (CD86 expression) and IL-12 production from mDCs. Enhancement in NK cell function by IL-15 is observed in HCMV-seropositive and -seronegative individuals
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