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