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

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_tex) 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.