Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses
Helen R. Wagstaffe, … , Eleanor M. Riley, Martin R. Goodier
Helen R. Wagstaffe, … , Eleanor M. Riley, Martin R. Goodier
Published April 21, 2020
Citation Information: J Clin Invest. 2020;130(7):3936-3946. https://doi.org/10.1172/JCI132438.
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Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses

Abstract

BACKGROUND NK cells are activated by innate cytokines and viral ligands to kill virus-infected cells. These functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined.METHODS The novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analyzed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen and in response to in vitro Ebola glycoprotein stimulation of PBMCs isolated before and after vaccination.RESULTS We show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein–induced activation of NK cells was dependent on accessory cells and TLR-4–dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whereas IFN-γ secretion was restricted by high concentrations of IL-10.CONCLUSION This study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola glycoprotein.TRIAL REGISTRATION ClinicalTrials.gov NCT02313077.FUNDING United Kingdom Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (grant 115861) and Crucell Holland (now Janssen Vaccines and Prevention B.V.), European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA).

Authors

Helen R. Wagstaffe, Elizabeth A. Clutterbuck, Viki Bockstal, Jeroen N. Stoop, Kerstin Luhn, Macaya Douoguih, Georgi Shukarev, Matthew D. Snape, Andrew J. Pollard, Eleanor M. Riley, Martin R. Goodier

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Figure 3

Less differentiated NK cells respond strongly to EBOV GP stimulation in vitro.

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Less differentiated NK cells respond strongly to EBOV GP stimulation in ...
NK cell IFN-γ (A) and CD107a (B) measured at 8 hours and CD25 (C) measured at 18 hours in response to medium alone and EBOV GP in baseline (visit 0) samples only, were analyzed according to NK cell differentiation subset determined by CD56 and CD57 expression (CD56bright, CD56dimCD57–, CD56dimCD57intermediate (int) and CD56dimCD57+) (n = 70). The proportion of CD25+ NK cell events per subset determined by back-gating is also shown as a pie chart (D). Graphs show 1 point per donor with a line representing the median. Comparisons across NK cell subsets were performed using 1-way ANOVA with Dunn’s correction for multiple comparisons and between conditions by Wilcoxon signed-rank test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.