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

Cell Metabolism
Nelson M LaMarcheMichael B Brenner

Abstract

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. NK1.1NEG cells almost exclusively produced IL-10 and other regulatory cytokines, while NK1.1POS iNKT cells predominantly produced IFNγ. Mechanistically, biochemical fractionation revealed that free fatty acids drive IL-10 production primarily in NK1.1NEG iNKT cells via the IRE1α-XBP1s arm of the unfolded protein response. Correspondingly, adoptive transfer of adipose tissue NK1.1NEG iNKT cells selectively restored metabolic function in obese mice. Further, we found an unexpected role for NK1.1POS 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.

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Citations

Aug 28, 2020·Frontiers in Endocrinology·Robert J van EijkerenEric Kalkhoven
Dec 29, 2020·Molecular Immunology·Elizabeth A Leadbetter, Mikael C I Karlsson
Jan 14, 2021·Immunological Reviews·Elizabeth A Leadbetter, Mikael C I Karlsson
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Dec 18, 2020·Frontiers in Immunology·Ali AminiPaul Klenerman
Mar 3, 2021·Genes & Development·Yun Sok Lee, Jerrold Olefsky
Mar 16, 2021·Immunometabolism·Emily L YaroszAjay Kumar
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Sep 27, 2021·The FEBS Journal·Xinmin QianWenwen Zeng
Nov 7, 2021·Nature Reviews. Immunology·W V Trim, L Lynch

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