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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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725009489 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Aprajita Tripathi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c6b500a00a814e8db4145a9676da591e |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-c6b500a00a814e8db4145a9676da591e2025-08-26T04:14:14ZengElsevierCell Reports2211-12472025-09-0144911617710.1016/j.celrep.2025.116177Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolismAprajita Tripathi0Debolina Dasgupta1Michael S. Dahabieh2Rachel Griffard-Smith3Anil Pant4Ashlyn Bugbee5Nanda Kumar Yellapu6Emily Burt7Ben H.Y. Choi8Abigail E. Ellis9Ryan D. Sheldon10Shailendra Giri11Devin Koestler12Russell G. Jones13Viveka Nand Yadav14Kalyani Pyaram15Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USADepartment of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USADepartment of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USADepartment of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USADepartment of Biology, Kansas State University, Manhattan, KS, USADepartment of Biology, Kansas State University, Manhattan, KS, USADepartment of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USADepartment of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USADepartment of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USAMass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USADepartment of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USADepartment of Neurology, Henry Ford Health, Detroit, MI, USADepartment of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USADepartment of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USADepartment of Pediatrics, Children’s Mercy Research Institute (CMRI), Kansas City, MO, USA; Department of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, MO, USA; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USADepartment of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725009489CP: ImmunologyCP: Metabolism |
| spellingShingle | 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 Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism Cell Reports CP: Immunology CP: Metabolism |
| title | Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism |
| title_full | Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism |
| title_fullStr | Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism |
| title_full_unstemmed | Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism |
| title_short | Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism |
| title_sort | nrf2 drives activation driven expansion of cd4 t cells by modulating glucose and glutamine metabolism |
| topic | CP: Immunology CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725009489 |
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