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

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 I(2) (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.