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

IF 27.7 1区医学 Q1 IMMUNOLOGY

Nature Immunology Pub Date : 2025-06-27 DOI:10.1038/s41590-025-02185-9

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

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引用次数: 0

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_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.

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前列环素受体PTGIR是CD8+ T细胞衰竭的nrf2依赖性调节因子

CD8+ T细胞耗竭（Tex）限制了癌症的免疫控制，但潜在的分子驱动因素尚不清楚。在本研究中，我们发现前列腺素I2（前列腺环素）受体PTGIR是T细胞衰竭的细胞内在调节剂。终端耗竭（Ttex） CD8+ T细胞的转录组学分析显示，核因子-红细胞2相关因子- 2 （NRF2）氧化应激反应途径的激活增加。增强NRF2活性（通过有条件地删除kelch样ech相关蛋白1 (KEAP1)）促进CD8+ T细胞中谷胱甘肽的产生，但加速终衰竭。NRF2上调PTGIR在CD8+ T细胞中的表达。在慢性感染和癌症模型中，沉默PTGIR表达可增强T细胞效应功能（即干扰素-γ和颗粒酶的产生），并限制Ttex细胞的发育。从机制上讲，PTGIR信号通路在诱导Tex细胞转录特征的同时损害T细胞代谢和细胞因子的产生。这些发现确定PTGIR作为nrf2依赖的免疫检查点，调节效应和耗尽CD8+ T细胞状态之间的平衡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Immunology 医学-免疫学

CiteScore

40.00

自引率

2.30%

发文量

248

审稿时长

4-8 weeks

期刊介绍： Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.