Nrf2 drives activation-driven expansion of CD4T cells by modulating glucose and glutamine metabolism.

Upon antigenic stimulation, CD4T 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 CD4T cells remains unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4T 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 CD4T cells. Mechanistically, elevated Nrf2 activity in activated CD4T cells increases chromatin accessibility and proliferation-associated gene expression. Metabolically, high Nrf2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support CD4T cell hyperproliferation. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4T cells by influencing their nutrient metabolism and gene expression.