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

Quirin Hammer,Timo Rückert,Chiara Romagnani,Josefine Dunst

doi:10.3389/fimmu.2017.01976

Abstract

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.

Highlights

Natural killer (NK) cells are lymphocytes required for proficient immunity against viral infections [1], and as members of the innate lymphoid cell family, NK cells are classically regarded part of the innate immune system [2]
Effector Responses of Adaptive NK Cells against Target Cells Are Amplified by Reprogrammed effector functions are a hallmark of adaptive NK cells and, in line with previous data [9, 12], only a minor fraction of adaptive NKG2C+ NK cells produced the NK-cell signature cytokine interferon (IFN)-γ after 24 h stimulation with IL-12 + 18 as compared to conventional NKG2C− NK cells (Figures 1A,B), suggesting that adaptive NK cells are largely insensitive to these pro-inflammatory cytokines as a single stimulus
The presence of IL-12 + 18 during target-cell stimulation consistently increased the frequency of IFN-γ+ as well as tumor necrosis factor (TNF)+ adaptive NK cells (Figures 1D,H), indicating that these pro-inflammatory cytokines can still function as costimulatory signals for adaptive NK cells

Summary

Introduction

Natural killer (NK) cells are lymphocytes required for proficient immunity against viral infections [1], and as members of the innate lymphoid cell family, NK cells are classically regarded part of the innate immune system [2]. Emerging experimental evidence suggest that NK cells can display adaptive-like features in response to inflammatory signals [3, 4], hapten challenge [5], and especially viral infection [6, 7]. Adaptive NK-cell responses are driven by human cytomegalovirus (HCMV) infection and are associated with the expansion of subsets expressing the activating receptor NKG2C [8]. Adaptive NKG2C+ NK cells in HCMV-seropositive individuals display skewed and narrow expression patterns of otherwise stochastically distributed killer Ig-like receptors, which is suggestive of oligoclonal or clonal-like expansion upon HCMV infection and parallels the pathogen-specific responses of T cells [9, 10]. The loss of DNA methylation at regulatory regions within the TNF and IFNG loci is IL-18 Costimulates Adaptive NK Cells peculiarly shared between adaptive NK cells and terminally differentiated T cells [11, 12], enabling robust cytokine production and highlighting adaptive traits at the molecular level

Methods

Results

Conclusion