Adaptive Natural Killer Cells Integrate Interleukin-18 during Target-Cell Encounter

Human cytomegalovirus (HCMV) infection induces adaptations in the natural killer (NK)-cell compartment. Expanded subsets of adaptive NK cells display potent effector functions against cellular targets, despite their apparent unresponsiveness to stimulation with classical dendritic cell-derived cytokines interleukin (IL)‑12 and IL‑18. However, it remains unclear whether adaptive NK cells have completely lost their ability to sense inflammation via IL‑12 and IL‑18 or whether these pro-inflammatory signals can be functionally integrated into defined contexts. Here, we demonstrate that adaptive NKG2C+ NK cells can be co-stimulated by the presence of pro-inflammatory cytokines during target cell-induced activation. Cytokine co-stimulation of adaptive NK cells resulted in elevated interferon (IFN)-gamma and tumor necrosis factor (TNF) production, which promoted protein expression of HLA class I and adhesion molecules as well as transcription of genes involved in antigen processing and anti-viral states in endothelial bystander cells in vitro. We further show that IL-18 drove co-stimulation in functional assays and was sufficient for elevated cytokine production in the absence of IL-12. Hence, adaptive NKG2C+ NK cells - although poorly responsive to IL‑12 and IL‑18 as an isolated stimulus - integrate IL‑18 as a co-stimulatory signal during target-cell encounter.