The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion.
| Title: | The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion. |
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| Authors: | Dahabieh MS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; DeCamp LM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Oswald BM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Kitchen-Goosen SM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Fu Z; Bioinformatics and Biostatistics Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Vos M; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Compton SE; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Longo J; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Foy NM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Williams KS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Ellis AE; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Johnson A; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Sodiya I; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Vincent M; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Lee H; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Yao C; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Wu T; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Sheldon RD; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Krawczyk CM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.; Jones RG; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA. russell.jones@vai.org.; Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA. russell.jones@vai.org. |
| Source: | Nature immunology [Nat Immunol] 2025 Jul; Vol. 26 (7), pp. 1139-1151. Date of Electronic Publication: 2025 Jun 27. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature America Inc Country of Publication: United States NLM ID: 100941354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2916 (Electronic) Linking ISSN: 15292908 NLM ISO Abbreviation: Nat Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York, NY : Nature America Inc. c2000- |
| MeSH Terms: | NF-E2-Related Factor 2*/metabolism ; NF-E2-Related Factor 2*/genetics ; NF-E2-Related Factor 2*/immunology ; CD8-Positive T-Lymphocytes*/immunology ; CD8-Positive T-Lymphocytes*/metabolism; Kelch-Like ECH-Associated Protein 1/genetics ; Kelch-Like ECH-Associated Protein 1/metabolism ; Animals ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Signal Transduction ; Humans ; Oxidative Stress ; T-Cell Exhaustion |
| Abstract: | CD8+ T cell exhaustion (Tex) limits immune control of cancer, but the underlying molecular drivers are unclear. In the present study, we identified the prostaglandin I2 (prostacyclin) receptor PTGIR as a cell-intrinsic regulator of T cell exhaustion. Transcriptomic profiling of terminally exhausted (Ttex) CD8+ T cells revealed increased activation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response pathway. Enhancing NRF2 activity (by conditional deletion of Kelch-like ECH-associated protein 1 (KEAP1)) boosts glutathione production in CD8+ T cells but accelerates terminal exhaustion. NRF2 upregulates PTGIR expression in CD8+ T cells. Silencing PTGIR expression enhances T cell effector function (that is, interferon-γ and granzyme production) and limits Ttex cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of Tex cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8+ T cell states.; (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: R.G.J. is a scientific advisor for Servier Pharmaceuticals and a member of the Scientific Advisory Board of Immunomet Therapeutics. R.G.J. and M.S.D. are inventors on a provisional patent application titled ‘Compositions of leukocytes with resistance to prostanoids and related methods of use’ (no. IP-00237). The other authors declare no competing interests. |
| Comments: | Update of: bioRxiv. 2024 Jun 28:2024.06.23.600279. doi: 10.1101/2024.06.23.600279.. (PMID: 38979360) |
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| Grant Information: | R01 AI165722 United States AI NIAID NIH HHS; AI154450 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); MFE-181903 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); R01 AI158294 United States AI NIAID NIH HHS; K99 AG056524 United States AG NIA NIH HHS; AI158294 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); R21AI153997 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); R21 AI153997 United States AI NIAID NIH HHS; RR210035 Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas); R00 AG056524 United States AG NIA NIH HHS; MFE-403514 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); AG056524 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging); DP2 AI154450 United States AI NIAID NIH HHS |
| Substance Nomenclature: | 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Kelch-Like ECH-Associated Protein 1) |
| Entry Date(s): | Date Created: 20250627 Date Completed: 20250630 Latest Revision: 20250704 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12208871 |
| DOI: | 10.1038/s41590-025-02185-9 |
| PMID: | 40579556 |
| Database: | MEDLINE |
Journal Article