The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion
CD8<sup>+</sup> T cell exhaustion (T<sub>ex</sub>) limits immune control of cancer, but the underlying molecular drivers are unclear. In the present study, we identified the prostaglandin I<sub>2</sub> (prostacyclin) receptor PTGIR as a cell-intrinsic regulator of T cell exhaustion. Transcriptomic profiling of terminally exhausted (T<sub>t</sub><sub>ex</sub>) CD8<sup>+</sup> 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<sup>+</sup> T cells but accelerates terminal exhaustion. NRF2 upregulates PTGIR expression in CD8<sup>+</sup> T cells. Silencing PTGIR expression enhances T cell effector function (that is, interferon-γ and granzyme production) and limits T<sub>tex</sub> cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of T<sub>ex</sub> cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8<sup>+</sup> T cell states.
Authors
- Hyoungjoo Lee (ORCID: https://orcid.org/0000-0003-3348-5270)
- Ibukunoluwa Sodiya
- Brandon M. Oswald (ORCID: https://orcid.org/0000-0002-4147-2915)
- Lisa M. DeCamp (ORCID: https://orcid.org/0000-0002-4682-7586)
- Connie M. Krawczyk (ORCID: https://orcid.org/0000-0002-2468-5986)
- Amy J. Johnson (ORCID: https://orcid.org/0000-0002-0306-4646)
- Shelby E. Compton
- Matthew Vos (ORCID: https://orcid.org/0009-0008-9669-4380)
- Michael A. Vincent (ORCID: https://orcid.org/0000-0002-0338-0534)
- Ryan D. Sheldon (ORCID: https://orcid.org/0000-0002-1573-9719)
- Russell G. Jones (ORCID: https://orcid.org/0000-0003-2250-4675)
- Joseph Longo (ORCID: https://orcid.org/0000-0002-9580-5105)
- Abigail E. Ellis (ORCID: https://orcid.org/0000-0002-8736-8283)
- Susan M. Kitchen-Goosen (ORCID: https://orcid.org/0000-0001-9291-056X)
- Tuoqi Wu (ORCID: https://orcid.org/0000-0002-4003-1034)
- Michael S. Dahabieh
- Kelsey S. Williams
- Chen Yao (ORCID: https://orcid.org/0000-0001-6852-5661)
- Zhen F. Fu (ORCID: https://orcid.org/0000-0001-6293-9329)
- Nicole M Foy
Institutions
- Van Andel Institute (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1038/s41590-025-02185-9
- Citations
- 12
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 9.57
Funders
- Cancer Research Institute
- Paul G. Allen Family Foundation
- American Federation for Aging Research
- V Foundation for Cancer Research
- Cancer Prevention and Research Institute of Texas
- Van Andel Research Institute
- University of Texas Southwestern Medical Center
- Canadian Institutes of Health Research
- National Institute on Aging
- National Institute of Allergy and Infectious Diseases