IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu
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引用次数: 0

摘要

本研究旨在探索代谢中间产物 L-2-hydroxyglutarate (L-2-HG) 与 T 细胞衰竭之间的潜在关联以及相关的内在机制。在这项研究中,我们调查了在特定条件下患者体内是否存在衰竭的 T 细胞(Tex):艾滋病病毒感染、慢性白血病和肝细胞癌。为了深入了解 Tex 的表观遗传学特征和转录组变化,我们结合使用了 RNA-seq 和 ATAC-seq 分析。为了评估 L-2-HG 对 Tex 线粒体功能、分化和抗肿瘤能力的影响,我们利用了体外细胞培养实验和动物肿瘤模型。我们观察到 Tex 的线粒体去极化和代谢功能障碍,同时伴随着代谢中间体 L-2-HG 水平的显著降低。此外,在 Tex 中还观察到了表观遗传特征的改变,包括 H3K27me3 丰度的大幅增加。用 L-2-HG 培养 Tex 可改善线粒体代谢、降低 H3K27me3 丰度并增强记忆 T 细胞分化。在小鼠黑色素瘤肿瘤模型中,L-2-HG 处理的 CD8+T 细胞用于采纳疗法可显著减少肿瘤体积,并明显增强 T 细胞的效应功能。研究显示,L-2-HG 通过对 Tex 进行表观遗传修饰而成为一种免疫代谢物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.

This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T cells (Tex) in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome alterations in Tex, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and anti-tumor capacity of Tex, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex, accompanied by a significant reduction in the metabolic intermediate L-2-HG level. Moreover, altered epigenetic characteristics was observed in Tex, including a substantial increase in H3K27me3 abundance. Culturing Tex with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In the mouse melanoma tumor model, L-2-HG-treated CD8+T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed L-2-HG acted as an immune metabolite through epigenetic modifications of Tex.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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