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Updated: Sep 17, 2025

Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion
Michael S Dahabieh1,2, Lisa M DeCamp1,2, Brandon M Oswald1,2
1Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
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.
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