Keap1-Nrf2 System Plays an Important Role in Invariant Natural Killer T Cell Development and Homeostasis

Abstract

Summary: Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) proteins work in concert to regulate the levels of reactive oxygen species (ROS). The Keap1-Nrf2 antioxidant system also participates in T cell differentiation and inflammation, but its role in innate T cell development and functions remains unclear. We report that T cell-specific deletion of Keap1 results in defective development and reduced numbers of invariant natural killer T (NKT) cells in the thymus and the peripheral organs in a cell-intrinsic manner. The frequency of NKT2 and NKT17 cells increases while NKT1 decreases in these mice. Keap1-deficient NKT cells show increased rates of proliferation and apoptosis, as well as increased glucose uptake and mitochondrial function, but reduced ROS, CD122, and Bcl2 expression. In NKT cells deficient in Nrf2 and Keap1, all these phenotypic and metabolic defects are corrected. Thus, the Keap1-Nrf2 system contributes to NKT cell development and homeostasis by regulating cell metabolism. : Keap1 and Nrf2 proteins work in concert to regulate redox balance in the cells. Pyaram et al. report that Keap1 governs NKT cell development and peripheral homeostasis by regulating proliferation and apoptosis. In an Nrf2-dependent manner, Keap1 also controls NKT cell metabolism, including glucose uptake and ROS. Keywords: innate T cells, cell metabolism, antioxidant system, NKT cells, reactive oxygen species