PT  - JOURNAL ARTICLE
AU  - Ajay Kumar
AU  - Emily L. Yarosz
AU  - Anthony Andren
AU  - Li Zhang
AU  - Costas A. Lyssiotis
AU  - Cheong-Hee Chang
TI  - Glutamine metabolism enables NKT cell homeostasis and function through the AMPK-mTORC1 signaling axis
AID  - 10.1101/2021.10.07.463490
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.07.463490
4099  - http://biorxiv.org/content/early/2021/10/09/2021.10.07.463490.short
4100  - http://biorxiv.org/content/early/2021/10/09/2021.10.07.463490.full
AB  - Cellular metabolism is essential in dictating conventional T cell development and function, but its role in natural killer T (NKT) cells has not been well studied. We have previously shown that NKT cells operate distinctly different metabolic programming from CD4 T cells, including a strict requirement for glutamine metabolism to regulate NKT cell homeostasis. However, the mechanisms by which NKT cells regulate glutamine metabolism for their homeostasis and effector functions remain unknown. In this study, we report that steady state NKT cells have higher glutamine levels than CD4 T cells and NKT cells increase glutaminolysis upon activation. Among its many metabolic fates, NKT cells use glutamine to fuel the tricarboxylic acid cycle and glutathione synthesis, and glutamine-derived nitrogen enables protein glycosylation via the hexosamine biosynthesis pathway (HBP). Each of these functions of glutamine metabolism was found to be critical for NKT cell survival and proliferation. Furthermore, we demonstrate that glutaminolysis and the HBP differentially regulate IL-4 and IFNγ production. Finally, glutamine metabolism appears to be controlled by AMP-activated protein kinase (AMPK)-mTORC1 signaling. These findings highlight a unique metabolic requirement of NKT cells which can be potentially serve as an effective immunotherapeutic agent against certain nutrient restricted tumors.Significance NKT cells get activated very early during an immune response and produce cytokines and chemokines, which further activate other immune cell types. Although metabolism regulates these functions in other T cell subsets, little is understood about how metabolic pathways are controlled in NKT cells. The present study shows that NKT cells metabolize the amino acid glutamine through two different branches of metabolism, which control NKT cell homeostasis and expansion in a similar manner but control cytokine production differently. This glutamine dependency seems to be regulated by AMP-activated protein kinase (AMPK), which is a central regulator of energy homeostasis. Together, our study demonstrates a unique metabolic profile of glutamine metabolism in NKT cells which could be harnessed for NKT cell-based immunotherapy.Competing Interest StatementC.A.L. has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in cancer, and targeting the GOT1-pathway as a therapeutic approach.