The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion

Michael S Dahabieh; Lisa M DeCamp; Brandon M Oswald; Susan M Kitchen-Goosen; Zhen Fu; Matthew Vos; Shelby E Compton; Joseph Longo; Nicole M Foy; Kelsey S Williams; Abigail E Ellis; Amy Johnson; Ibukunoluwa Sodiya; Michael Vincent; Hyoungjoo Lee; Chen Yao; Tuoqi Wu; Ryan D Sheldon; Connie M Krawczyk; Russell G Jones

doi:10.1038/s41590-025-02185-9

The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8⁺ T cell exhaustion

Nat Immunol. 2025 Jun 27. doi: 10.1038/s41590-025-02185-9. Online ahead of print.

Authors

Michael S Dahabieh^{1

2}, Lisa M DeCamp^{1

2}, Brandon M Oswald^{1

2}, Susan M Kitchen-Goosen^{1

2}, Zhen Fu³, Matthew Vos^{1

2}, Shelby E Compton^{1

2}, Joseph Longo^{1

2}, Nicole M Foy^{1

2}, Kelsey S Williams^{1

2}, Abigail E Ellis⁴, Amy Johnson⁴, Ibukunoluwa Sodiya^{1

4}, Michael Vincent^{1

4}, Hyoungjoo Lee^{1

4}, Chen Yao^{5

6}, Tuoqi Wu^{5

7}, Ryan D Sheldon^{1

4}, Connie M Krawczyk^{1

2}, Russell G Jones^{8

9}

Affiliations

¹ Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
² Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA.
³ Bioinformatics and Biostatistics Core Facility, Van Andel Institute, Grand Rapids, MI, USA.
⁴ Mass Spectrometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.
⁵ Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA. russell.jones@vai.org.
⁹ Metabolism and Nutrition (MeNu) Program, Van Andel Institute, Grand Rapids, MI, USA. russell.jones@vai.org.

PMID: 40579556
DOI: 10.1038/s41590-025-02185-9

Abstract

CD8⁺ T cell exhaustion (T_ex) 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 (T_t_ex) 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 T_tex cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of T_ex cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8⁺ T cell states.

Abstract

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