NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.
| Title: | NRF2-dependent regulation of the prostacyclin receptor PTGIR drives 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.; 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.; 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.; 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.; Jones RG; 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. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 28. Date of Electronic Publication: 2024 Jun 28. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| 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 (Texterm) 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. |
| Competing Interests: | Competing interests: RGJ is a scientific advisor for Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics. |
| Comments: | Update in: Nat Immunol. 2025 Jul;26(7):1139-1151. doi: 10.1038/s41590-025-02185-9.. (PMID: 40579556) |
| Grant Information: | R01 AI165722 United States AI NIAID NIH HHS; R01 AI158294 United States AI NIAID NIH HHS; K99 AG056524 United States AG NIA NIH HHS; R21 AI153997 United States AI NIAID NIH HHS; R00 AG056524 United States AG NIA NIH HHS; DP2 AI154450 United States AI NIAID NIH HHS |
| Entry Date(s): | Date Created: 20240709 Latest Revision: 20250703 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11230227 |
| DOI: | 10.1101/2024.06.23.600279 |
| PMID: | 38979360 |
| Database: | MEDLINE |
Journal Article; Preprint