Nrf2 drives activation-driven expansion of CD4⁺T cells by modulating glucose and glutamine metabolism

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 factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4⁺T cells remains 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 negative regulator Keap1, enhances early activation and interleukin-2 (IL-2) expression, upregulates T cell receptor (TCR) signaling, and increases activation-driven expansion of CD4⁺T cells. Mechanistically, elevated Nrf2 activity in activated CD4⁺T cells increases chromatin accessibility and proliferation-associated gene expression. Metabolically, high Nrf2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support CD4⁺T cell hyperproliferation. 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 and gene expression.