Nrf2 regulates activation driven-expansion of CD4+T-cells by differentially modulating glucose and glutamine metabolism [ATAC-Seq]

Upon antigenic stimulation, CD4+T-cells undergo clonal expansion elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine The nuclear factor erythroid 2-related factor2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remain unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4+T-cells, with elevated expression during early activation followed by a decline. T-cell-specific constitutive activation of Nrf2 by deletion of its regulator Keap1, enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven expansion of CD4+T-cells. Metabolically, high Nr2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support increased CD4+T-cell proliferation. Mechanistically, elevated Nrf2 activity in activated CD4+T-cells leads to increased chromatin accessibility and proliferation-associated gene expression. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4+T-cells by influencing their nutrient metabolism.