IL-27 promotes NK cell effector functions via Maf-Nrf2 pathway during influenza infection

Abstract

Influenza virus targets epithelial cells in the upper respiratory tract. Natural Killer (NK) cell-mediated early innate defense responses to influenza infection include the killing of infected epithelial cells and generation of anti-viral cytokines including interferon gamma (IFN-γ). To date, it is unclear how the underlying cytokine milieu during infection regulates NK cell effector functions. Our data show during influenza infection myeloid cell-derived IL-27 regulates the early-phase effector functions of NK cells in the bronchioalveolar and lung tissue. Lack of IL-27R (Il27ra−/−) or IL-27 (Ebi3−/−) resulted in impaired NK cell effector functions including the generation of anti-viral IFN-γ responses. We identify CD27+CD11b+ NK cells as the primary subset that expresses IL-27R, which predominantly produces IFN-γ within the upper respiratory tract of the infected mice. IL-27 alone was incapable of altering the effector functions of NK cells. However, IL-27 sensitizes NK cells to augment both in vitro and in vivo responses mediated via the NKG2D receptor. This ‘priming’ function of IL-27 is mediated partly via transcriptional pathways regulated by Mafs and Nrf2 transcriptionally regulating TFAM and CPT1. Our data for the first time establishes a novel role for IL-27 in regulating early-phase effector functions of NK cells during influenza infection.

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…CMV encodes for proteins directly targeting infected host cell metabolism, 253,254 making metabolic reprogramming by CMV difficult to generalize to other viruses. Finally, IAV infection upregulates Il‐27R on the NK surface, and NK cells require Il‐27–mediated induction of musculoaponeurotic fibrosarcoma F (Maf‐F) and nuclear factor erythroid 2–related factor 2 (Nrf2) to increase gene expression of γ‐glutamylcysteine ligase, mitochondrial transcription factor A, and carnitine palmitoyltransferase required for NK effector function in IAV infection 255 . This is the sole report identifying specific metabolic regulators necessary for NK activity in IAV.…”

“…IFN-γ production appears to require glycolysis unless the appropriate cytokines are present at the right concentrations to override this metabolic requirement. 255 This is the sole report identifying specific metabolic regulators necessary for NK activity in IAV.…”

Deficient IL-2 Produced by Activated CD56+ T Cells Contributes to Impaired NK Cell-Mediated ADCC Function in Chronic HIV-1 Infection

“…A study have reported that IL-18 could augment IFN-γ production and ADCC function of NK cells activated through Fc receptors in vitro , and could synergy with IL-2, IL-15, and IL-21 to potentiates NK cell effector function during innate and adaptive immune responses (29). IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions (30). It is unfortunately that IL-18 and IL-27 were not included in our present study.…”

Flavonoids Activation of the Transcription Factor Nrf2 as a Hypothesis Approach for the Prevention and Modulation of SARS-CoV-2 Infection Severity

“…A recent study investigating the myeloid cell-derived IL-27 signaling reported that IL-27 mediates the regulation of NK cells effector responses. Subsequent to influenza infection, WT mice presented CD27 + CD11b + effector NK cells in the alveolar space and lung tissue, which was not observed in IL27ra −/− mice, suggesting a critical role for IL-27 in regulating this NK subset [98]. It has also been reported that in NK cells, the expression of CD27 may determine the ability of cell migration, suggesting that IL-27 may promote the trafficking of a subset of NK cells to the infection site [99,100].…”

“…NK cells from IL27ra −/− mice animals showed reduced levels of MafF expression, which is one of the Nrf2 interaction sites for the transcription of cytoprotective genes [98]. Therefore IL-27 seems to have a critical function in NK cell-mediated functions through transcriptional pathways regulated by Mafs and Nrf2 and may play a role in the regulation of adaptive immune response that can determine the pathophysiological outcome after infection by influenza [98].…”