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

Nelson M LaMarche; Harry Kane; Ayano C Kohlgruber; Han Dong; Lydia Lynch; Michael B Brenner

doi:10.1016/j.cmet.2020.05.017

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

Cell Metab. 2020 Aug 4;32(2):243-258.e6. doi: 10.1016/j.cmet.2020.05.017. Epub 2020 Jun 8.

Authors

Nelson M LaMarche¹, Harry Kane², Ayano C Kohlgruber³, Han Dong⁴, Lydia Lynch⁵, Michael B Brenner⁶

Affiliations

¹ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Program in Immunology, Harvard Medical School, Boston, MA, USA.
² Trinity Biomedical Science Institute, Trinity College Dublin, Dublin, Ireland.
³ Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA.
⁵ Trinity Biomedical Science Institute, Trinity College Dublin, Dublin, Ireland; Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Program in Immunology, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: mbrenner@research.bwh.harvard.edu.

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. NK1.1^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.

Keywords: ER stress; NK cells; adipose tissue; iNKT cells; inflammation; lipids; macrophages; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism*
Animals
Endoplasmic Reticulum Stress
Homeostasis
Interferon-gamma / deficiency
Interferon-gamma / metabolism*
Interleukin-10 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Natural Killer T-Cells / metabolism*

Substances

IFNG protein, mouse
IL10 protein, mouse
Interleukin-10
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding