The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype

Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease in which the fatty liver becomes chronically inflamed. Here, we report that in the livers of both humans and mice suffering from NAFLD, NK cells are less able to degranulate. In mice, this is associated with a decreased ability to kill cancerous targets both in vitro and in vivo. On the other hand, perforin-deficient mice suffer from less severe NAFLD, suggesting that perforin-mediated killing is harmful in the obese liver and that the reduction in NK cell cytotoxicity may therefore be protective. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of inhibitory receptors expressed by ILC1, and an altered metabolic profile mimicking that of ILC1. This conversion of NK cells to a less cytotoxic ILC1-like phenotype is at least partially mediated by high levels of TGF{beta} produced in the obese liver.