The metabolic signature of adaptive NK cells is maintained during chronic viral hepatitis

The human NK-cell repertoire is highly diverse. In particular, latent HCMV infection has been shown to induce the formation of adaptive CD56dim NK-cell subsets that can be separated from conventional subsets by expression of the activating receptor NKG2C. Conventional and adaptive NK-cell subsets differ in their effector and survival characteristics with adaptive NK cells being long-lived. In general, metabolic reprogramming is important to adapt to the bioenergetic demands of effector cell function and long-term survival of immune cells. This raises the question whether adaptive and conventional NK-cell subsets differ in their metabolic signatures related to their distinct characteristics. In addition, only little is known about the impact of chronic infection on the metabolic programme of human NK cells.

To address these questions we analysed the metabolic profiles of circulating conventional (NKG2C-CD56dim) and adaptive (NKG2C+CD56dim) NK-cell subsets obtained from healthy donors (n = 20) and patients chronically infected with Hepatitis B virus (HBV; n = 20) or Hepatitis C virus (HCV; n = 20). For this, we have assessed glucose uptake, mitochondrial characteristics as mitochondrial mass and membrane potential and autophagic activity by multicolour flow cytometry.

Our analyses revealed that conventional NKG2C-CD56dim NK cells display a significantly higher capacity for glucose uptake compared to adaptive NKG2C+CD56dim NK cells. Adaptive NKG2C+CD56dim NK cells, however, showed a relative increase in intact mitochondria reflected by higher mitochondrial membrane potential compared to conventional NKG2C-CD56dim NK cells while mitochondrial mass and autophagic activity were similar. Importantly, these metabolic signatures of conventional NKG2C-CD56dim NK cells versus adaptive NKG2C+CD56dim NK cells was maintained and not altered during chronic infection with HBV and HCV.

In sum, our data demonstrate that conventional NKG2C-CD56dim NK cells use glycolysis to meet the bioenergetic demands suggesting a non-quiescent state of ongoing cell turn-over with the requirement of increasing the biomass. In contrast, adaptive NKG2C+CD56dim NK cells represent metabolically quiescent subsets as reflected by a high fraction of cells with intact mitochondria, that is probably favourable for long-term survival. Of note, human conventional and adaptive NK-cell subsets seem to be metabolically reprogrammed on an intrinsic level since the different inflammatory environments in chronic HBV and HCV infection do not affect metabolic signatures.