{"doi":"10.1016/j.celrep.2025.116177","title":"Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism","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.","journal":"Cell Reports","year":2025,"id":520048,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1048314,"name":"Debolina Dasgupta","orcid":"0000-0002-4953-8026","position":1,"is_corresponding":false},{"id":1019141,"name":"Michael S. Dahabieh","orcid":null,"position":2,"is_corresponding":false},{"id":1389069,"name":"Rachel Griffard","orcid":"0000-0002-3330-695X","position":3,"is_corresponding":false},{"id":489651,"name":"Anil Pant","orcid":null,"position":4,"is_corresponding":false},{"id":1333076,"name":"Ashlyn Bugbee","orcid":null,"position":5,"is_corresponding":false},{"id":1019692,"name":"Nanda Kumar Yellapu","orcid":"0000-0002-3095-6375","position":6,"is_corresponding":false},{"id":1186453,"name":"Emily Burt","orcid":"0000-0001-9881-5002","position":7,"is_corresponding":false},{"id":1333077,"name":"Ben H. Choi","orcid":null,"position":8,"is_corresponding":false},{"id":1202485,"name":"Abigail E. Ellis","orcid":"0000-0002-8736-8283","position":9,"is_corresponding":false},{"id":503196,"name":"Ryan D. Sheldon","orcid":"0000-0002-1573-9719","position":10,"is_corresponding":false},{"id":483230,"name":"Shailendra Giri","orcid":"0000-0002-7123-829X","position":11,"is_corresponding":false},{"id":341806,"name":"Devin C. Koestler","orcid":"0000-0002-0598-0146","position":12,"is_corresponding":false},{"id":232805,"name":"Russell G. Jones","orcid":"0000-0003-2250-4675","position":13,"is_corresponding":false},{"id":302155,"name":"Viveka Nand Yadav","orcid":"0009-0001-5354-3717","position":14,"is_corresponding":false},{"id":854603,"name":"Kalyani Pyaram","orcid":"0000-0003-2744-7470","position":15,"is_corresponding":false},{"id":1049016,"name":"Aprajita Tripathi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T02:49:23.618703Z","pmid":"40857154","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}