Glutamine addiction in NKT cells is regulated by AMPK-mTORC1 axis

Abstract 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 IFNg 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 diseases. This work was supported in part by National Institutes of Health Grants R01 AI121156 and R01 AI148289 (to C-H.C.).