Glutamine metabolism drives NKT cell homeostasis and function

Abstract

Abstract Cellular metabolism is essential in dictating T cell development and function, but its role in natural killer T (NKT) cells has not been well studied. Activated CD4 T cells undergo a metabolic switch from oxidative to glycolytic metabolism to fuel their proliferation and effector function. We have previously shown that NKT cells operate distinctly different metabolic programming from CD4 T cells. We found that, unlike CD4 T cells, NKT cells rely more on glutamine for their homeostasis. In fact, we observed that resting NKT cells have higher levels of glutamine-derived metabolites than conventional CD4 T cells. However, the precise mechanisms by which NKT cells use glutamine for their proliferation and cytokine production remain unknown. Glutamine is metabolized into glutamate and then into alpha-ketoglutarate (α-KG) and glutathione (GSH). Using the pathway specific inhibitors revealed that NKT cells rely on both pathways for cell homeostasis, but cytokine production is associated with α-KG production. These glutamine oxidation processes control optimal mTORC1 activity and mitochondrial functions. Importantly, we observed a novel role of 5′ AMP-activated protein kinase (AMPK) in regulating glutamine metabolism in NKT cells. Taken together, glutamine metabolism is essential for NKT cell homeostasis and cytokine production.