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

作者：Michael S. Dahabieh, Lisa M. DeCamp, Brandon M. Oswald, Susan M. Kitchen-Goosen, Zhen F. Fu, Matthew Vos, Shelby E. Compton, Joseph Longo, Nicole M Foy, Kelsey S. Williams, Abigail E. Ellis, Amy J. Johnson, Ibukunoluwa Sodiya, Michael A. Vincent, Hyoungjoo Lee, Chen Yao, Tuoqi Wu, Ryan D. Sheldon, Connie M. Krawczyk, Russell G. Jones · 发表于：Nature Immunology · 年份：2025 · DOI：10.1038/s41590-025-02185-9 · 被引用次数：21 · 研究领域：Immune Cell Function and Interaction、Genomics, phytochemicals, and oxidative stress、Cancer Immunotherapy and Biomarkers

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. Targeting CD8+ T cell exhaustion is a strategy to enhance immune checkpoint inhibition and to fight cancer. Here the authors show a NRF2-dependent role for the prostaglandin I2 receptor PTGIR in controlling T cell exhaustion.