{"doi":"10.1101/2024.06.23.600279","title":"NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion","abstract":"Abstract The progressive decline of CD8 T cell effector function—also known as terminal exhaustion—is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Tex term ) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1 + TIM-3 + ) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states. One Sentence Summary The KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor, Ptgir .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485613,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":993224,"name":"Lisa M. DeCamp","orcid":"0000-0002-4682-7586","position":1,"is_corresponding":false},{"id":496126,"name":"Brandon M. Oswald","orcid":"0000-0002-4147-2915","position":2,"is_corresponding":false},{"id":496128,"name":"Susan M. Kitchen-Goosen","orcid":"0000-0001-9291-056X","position":3,"is_corresponding":false},{"id":1328611,"name":"Zhen F. Fu","orcid":"0000-0001-6293-9329","position":4,"is_corresponding":false},{"id":1209684,"name":"Matthew Vos","orcid":"0009-0008-9669-4380","position":5,"is_corresponding":false},{"id":993791,"name":"Shelby E. Compton","orcid":null,"position":6,"is_corresponding":false},{"id":473883,"name":"Joseph Longo","orcid":"0000-0002-9580-5105","position":7,"is_corresponding":false},{"id":232803,"name":"Kelsey S. Williams","orcid":"0000-0002-4163-5075","position":8,"is_corresponding":false},{"id":1202485,"name":"Abigail E. Ellis","orcid":"0000-0002-8736-8283","position":9,"is_corresponding":false},{"id":395711,"name":"Amy J. Johnson","orcid":"0000-0002-0306-4646","position":10,"is_corresponding":false},{"id":1329119,"name":"Ibukunoluwa Sodiya","orcid":null,"position":11,"is_corresponding":false},{"id":1009753,"name":"Michael A. Vincent","orcid":"0000-0002-0338-0534","position":12,"is_corresponding":false},{"id":329995,"name":"Hyoungjoo Lee","orcid":"0000-0003-3348-5270","position":13,"is_corresponding":false},{"id":503196,"name":"Ryan D. Sheldon","orcid":"0000-0002-1573-9719","position":14,"is_corresponding":false},{"id":984137,"name":"Connie M. Krawczyk","orcid":"0000-0002-2468-5986","position":15,"is_corresponding":false},{"id":412055,"name":"Yao Chen","orcid":"0000-0001-5460-0149","position":16,"is_corresponding":false},{"id":623483,"name":"Tuoqi Wu","orcid":"0000-0002-4003-1034","position":17,"is_corresponding":false},{"id":232805,"name":"Russell G. Jones","orcid":"0000-0003-2250-4675","position":18,"is_corresponding":false},{"id":1019141,"name":"Michael S. Dahabieh","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:07:52.536246Z","pmid":"38979360","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":[]}