Keap1-Nrf2 system controls cellular metabolism to govern NKT cell homeostasis and effector functions

Abstract

Abstract Kelch-like ECH-associated protein (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) proteins work in concert as anti-oxidant system to regulate reactive oxygen species (ROS) levels. Additionally, Keap1-Nrf2 system has been shown to play a role in T cell-mediated inflammation but its role for maintenance and function of innate T cells is unclear. Using mice with T-cell specific deletion of Keap1 (KO) leading to higher Nrf2 activity, we recently reported that Keap1-Nrf2 system plays an essential role in the development and homeostasis of invariant natural killer T (NKT) cells. At steady state, KO NKT cells show increased rates of proliferation as well as apoptosis together with altered cell metabolism involving higher glucose uptake, glucose transporter-1 expression, mitochondrial mass and mitochondrial potential but lower ROS than WT NKT cells. Interestingly, upon activation with specific ligand a-GalCer, KO NKT cells proliferated lesser than WT NKT cells. Gene expression data indicated higher glycolysis and lower glutaminolysis in activated KO NKT than WT NKT cells. Further, unstimulated WT NKT cells were found to have elevated levels of glutamine and glutamate. NKT cells stimulated in the absence of glutamine survived and proliferated poorly but had no effect on cytokine production suggesting the importance of glutamine metabolism and keeping a check on glycolysis for the homeostasis and proliferation of NKT cells. Overall, our findings indicate that, via Nrf2, Keap1 positively regulates glutaminolysis and negatively regulates glycolysis to maintain NKT cell homeostasis and promote activation-driven proliferation. Here, we report a yet unknown role of Keap1-Nrf2 system in the cell metabolism of T cells.