Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice.

ABSTRACT

The nuclear receptors liver X receptor α (LXRα) and LXRß are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/ß in hepatic NKT cells remains unknown. In this study, we examined the role of LXRα and LXRß in NKT cells using mice deficient for LXRα and/or LXRß, and found that hepatic invariant NKT (iNKT) cells are drastically decreased in LXRα/ß-KO mice. Cytokine production stimulated by the iNKT cell activator α-galactosylceramide was impaired in LXRα/ß-KO hepatic mononuclear cells and in LXRα/ß-KO mice. iNKT cell-mediated antitumor effect was also disturbed in LXRα/ß-KO mice. LXRα/ß-KO mice transplanted with wild-type bone marrow showed decreased iNKT cells in the liver and spleen. The thymus of LXRα/ß-KO mice showed a decreased population of iNKT cells. In conclusion, LXRα and LXRß are essential for NKT cell-mediated immunity, such as cytokine production and hepatic antitumor activity, and are involved in NKT cell development in immune tissues, such as the thymus.