Distinct iNKT Cell Populations Use IFNγ or ER Stress-Induced IL-10 to Control Adipose Tissue Homeostasis

Adipose tissue invariant natural killer T (iNKT) cells are phenotypically different from other iNKT cells because they produce IL-10 and control metabolic homeostasis. Why that is the case is unclear. Here, using single-cell RNA sequencing, we found several adipose iNKT clusters, which we grouped into two functional populations based on NK1.1 expression. NK1.1^NEG cells almost exclusively produced IL-10 and other regulatory cytokines, while NK1.1^POS iNKT cells predominantly produced IFNγ. Mechanistically, biochemical fractionation revealed that free fatty acids drive IL-10 production primarily in NK1.1^NEG iNKT cells via the IRE1α-XBP1s arm of the unfolded protein response. Correspondingly, adoptive transfer of adipose tissue NK1.1^NEG iNKT cells selectively restored metabolic function in obese mice. Further, we found an unexpected role for NK1.1^POS iNKT cells in lean adipose tissue, as IFNγ licenses natural killer cell-mediated macrophage killing to limit pathological macrophage expansion. Together, these two iNKT cell populations utilize non-redundant pathways to preserve metabolic integrity.