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

Document Type

Article

Publication Date

9-23-2025

Publication Title

Cell Rep

Abstract

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.

Medical Subject Headings

NF-E2-Related Factor 2; Glutamine; CD4-Positive T-Lymphocytes; Glucose; Animals; Mice; Lymphocyte Activation; Cell Proliferation; Kelch-Like ECH-Associated Protein 1; Mice, Inbred C57BL; Receptors, Antigen, T-Cell; Signal Transduction; Interleukin-2

PubMed ID

40857154

Volume

44

Issue

9

First Page

116177

Last Page

116177

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