Abstract
The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift toward a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.
Highlights
Natural killer (NK) cells are innate lymphoid cells that recognize and kill virally infected and cancerous cells
We did not observe any difference in NK cell or ILC1 frequencies in the spleens or livers of obese compared to lean mice (Figure 1A) but NK cells isolated from the livers of mice that had been kept on the obesogenic diet for 12 weeks degranulated less than those from the livers of their lean littermates (Figure 1B)
We found a significant reduction in the expression of perforin by NK cells in the livers of obese mice, that we did not detect in splenic NK cells (Figure 1C)
Summary
Natural killer (NK) cells are innate lymphoid cells that recognize and kill virally infected and cancerous cells. It has recently come to light that, in tissues, cells defined in this way contain at least two distinct populations: circulating, or conventional, NK cells that are CD49a−CD49b+ and tissue-resident NK-like cells that are CD49a+CD49b− [1]. These have been called either tissue-resident NK cells or innate lymphoid cells, type 1 (ILC1): here, we call them ILC1 [2]. CD56− cells that display one of the proposed phenotypes for human ILC1 [4] have been reported in human liver [5]. The finding that Lin− NK1.1+ cells in mouse and CD3−CD56+ cells in human livers are heterogeneous populations means that it is necessary to re-examine the roles of these cells, distinguishing between NK and ILC1 or resident subpopulations
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