Scholarlink

<p>CD8<sup>+</sup> T cell exhaustion (T<sub>ex</sub>) limits immune control of cancer, but the underlying molecular drivers are unclear. In the present study, we identified the prostaglandin I<sub>2</sub> (prostacyclin) receptor PTGIR as a cell-intrinsic regulator of T cell exhaustion. Transcriptomic profiling of terminally exhausted (T<sub>t</sub><sub>ex</sub>) CD8<sup>+</sup> 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<sup>+</sup> T cells but accelerates terminal exhaustion. NRF2 upregulates PTGIR expression in CD8<sup>+</sup> T cells. Silencing PTGIR expression enhances T cell effector function (that is, interferon-γ and granzyme production) and limits T<sub>tex</sub> cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of T<sub>ex</sub> cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8<sup>+</sup> T cell states.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月27日

查看全文
  • Michael S. Dahabieh,
  • Lisa M. DeCamp,
  • Brandon M. Oswald,
  • Susan M. Kitchen-Goosen,
  • Zhen Fu,
  • Matthew Vos,
  • Shelby E. Compton,
  • Joseph Longo,
  • Nicole M. Foy,
  • Kelsey S. Williams,
  • Abigail E. Ellis,
  • Amy Johnson,
  • Ibukunoluwa Sodiya,
  • Michael Vincent,
  • Hyoungjoo Lee,
  • Chen Yao,
  • Tuoqi Wu,
  • Ryan D. Sheldon,
  • Connie M. Krawczyk,
  • Russell G. Jones

摘要

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.