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

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

Summary: 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 modulat...

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Main Authors: Aprajita Tripathi, Debolina Dasgupta, Michael S. Dahabieh, Rachel Griffard-Smith, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Emily Burt, Ben H.Y. Choi, Abigail E. Ellis, Ryan D. Sheldon, Shailendra Giri, Devin Koestler, Russell G. Jones, Viveka Nand Yadav, Kalyani Pyaram
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Cell Reports
Subjects:
CP: Immunology
CP: Metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725009489
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Summary:Summary: 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.
ISSN:2211-1247

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