Journal
FRONTIERS IN IMMUNOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2017.01976
Keywords
human natural killer cells; adaptive natural killer cells; NKG2C; interleukin-18; costimulation
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Funding
- Leibniz ScienceCampus Chronic Inflammation
- German Research Foundation (DFG) [SFB 650, RO3565/2-1, RO3565/4-1]
- DFG [RO 3565/1-1]
- Leibniz Association (Leibniz Graduate School for Rheumatology)
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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 costimulated by the presence of pro-inflammatory cytokines during target cell-induced activation. Cytokine costimulation 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 antiviral states in endothelial bystander cells in vitro. We further show that IL-18 drove costimulation 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 costimulatory signal during target-cell encounter.
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