NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function

Ajay Kumar; Emily L Yarosz; Anthony Andren; Li Zhang; Costas A Lyssiotis; Cheong-Hee Chang

doi:10.1016/j.celrep.2022.111516

NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function

Cell Rep. 2022 Oct 25;41(4):111516. doi: 10.1016/j.celrep.2022.111516.

Authors

Ajay Kumar¹, Emily L Yarosz², Anthony Andren³, Li Zhang³, Costas A Lyssiotis⁴, Cheong-Hee Chang⁵

Affiliations

¹ Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, Ann Arbor, MI 48109, USA. Electronic address: ajkumar@umich.edu.
² Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, Ann Arbor, MI 48109, USA; Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: heechang@umich.edu.

Abstract

Natural killer T (NKT) cells operate distinctly different metabolic programming from CD4 T cells, including a strict requirement for glutamine to regulate cell homeostasis. However, the underlying mechanisms remain unknown. Here, we report that at a steady state, NKT cells have higher glutamine levels than CD4 T cells and that NKT cells increase glutaminolysis on activation. Activated NKT cells use glutamine to fuel the tricarboxylic acid cycle and glutathione synthesis. In addition, glutamine-derived nitrogen enables protein glycosylation via the hexosamine biosynthesis pathway (HBP). Each of these branches of glutamine metabolism seems to be critical for NKT cell homeostasis and mitochondrial functions. Glutaminolysis and HBP differentially regulate interleukin-4 (IL-4) and interferon γ (IFNγ) production. Glutamine metabolism appears to be controlled by AMP-activated protein kinase (AMPK)-mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight a distinct metabolic requirement of NKT cells compared with CD4 T cells, which may have therapeutic implications in the treatment of certain nutrient-restricted diseases.

Keywords: CP: Immunology; HBP; PPP; ROS; glutathione; glycosylation; metabolism.

Publication types

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

MeSH terms

AMP-Activated Protein Kinases / metabolism
Glutamine / metabolism
Glutathione / metabolism
Hexosamines / metabolism
Homeostasis
Interferon-gamma / metabolism
Interleukin-4 / metabolism
Mechanistic Target of Rapamycin Complex 1 / metabolism
Natural Killer T-Cells* / metabolism
Nitrogen / metabolism
Phenotype
TOR Serine-Threonine Kinases / metabolism

Substances

Interleukin-4
Glutamine
AMP-Activated Protein Kinases
Interferon-gamma
Hexosamines
TOR Serine-Threonine Kinases
Mechanistic Target of Rapamycin Complex 1
Nitrogen
Glutathione

Abstract

Publication types

MeSH terms

Substances

Grants and funding