Altered lipid metabolites accelerate early dysfunction of T cells in HIV-infected rapid progressors by impairing mitochondrial function.
Altered lipid metabolites accelerate early dysfunction of T cells in HIV-infected rapid progressors by impairing mitochondrial function.
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脂质代谢物的改变通过损害线粒体功能加速 HIV 感染快速进展者 T 细胞的早期功能障碍
DOI：
10.3389/fimmu.2023.1106881
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发表时间：
2023
影响因子：
7.3
通讯作者：
Shang, Hong
中科院分区：
文献类型：
--
作者：
Li, Si-Yao;Yin, Lin-Bo;Ding, Hai-Bo;Liu, Mei;Lv, Jun-Nan;Li, Jia-Qi;Wang, Jing;Tang, Tian;Fu, Ya-Jing;Jiang, Yong-Jun;Zhang, Zi-Ning;Shang, Hong
关键词：
HIV感染中免疫系统损伤的复杂机制尚未完全了解。HIV感染的“快速进展者”（RP）在HIV感染早期对免疫系统有严重损害，这为研究HIV与免疫系统之间的相互作用提供了“放大”的机会。在这项研究中，入组了44名早期HIV感染患者（在过去6个月内记录了HIV感染）。通过研究23名RP（感染1年内CD 4 + T细胞计数< 350个细胞/μl）和21名“正常进展者”（NP;感染1年后CD 4 + T细胞计数> 500个细胞/μl）的血浆，鉴定出11种脂质代谢物，可以使用无监督聚类方法将大多数RP与NP区分开来。其中，长链脂肪酸二十碳烯酸酯显著抑制细胞因子的增殖和分泌，并诱导CD 4+和CD 8 + T细胞中TIM-3的表达。二十碳烯酸还增加了活性氧（ROS）水平，降低了T细胞的耗氧率（OCR）和线粒体质量，表明线粒体功能受损。此外，我们发现二十碳烯酸诱导T细胞中的p53表达，并且抑制p53有效地降低了T细胞中的线粒体ROS。更重要的是，用靶向细胞的抗氧化剂mito-TEMPO治疗T细胞恢复了二十碳烯酸盐诱导的T细胞功能障碍。这些数据表明，脂质代谢物二十碳烯酸通过诱导p53转录增加线粒体ROS来抑制免疫T细胞功能。我们的研究结果提供了一个新的机制，代谢物调节效应T细胞的功能，并提供了一个潜在的治疗目标，恢复T细胞功能在HIV感染。
The complex mechanism of immune-system damage in HIV infection is incompletely understood. HIV-infected “rapid progressors” (RPs) have severe damage to the immune system early in HIV infection, which provides a “magnified” opportunity to study the interaction between HIV and the immune system. In this study, forty-four early HIV-infected patients (documented HIV acquisition within the previous 6 months) were enrolled. By study the plasma of 23 RPs (CD4+ T-cell count < 350 cells/µl within 1 year of infection) and 21 “normal progressors” (NPs; CD4+ T-cell count > 500 cells/μl after 1 year of infection), eleven lipid metabolites were identified that could distinguish most of the RPs from NPs using an unsupervised clustering method. Among them, the long chain fatty acid eicosenoate significantly inhibited the proliferation and secretion of cytokines and induced TIM-3 expression in CD4+ and CD8+ T cells. Eicosenoate also increased levels of reactive oxygen species (ROS) and decreased oxygen consumption rate (OCR) and mitochondrial mass in T cells, indicating impairment in mitochondrial function. In addition, we found that eicosenoate induced p53 expression in T cells, and inhibition of p53 effectively decreased mitochondrial ROS in T cells. More importantly, treatment of T cells with the mitochondrial-targeting antioxidant mito-TEMPO restored eicosenoate-induced T-cell functional impairment. These data suggest that the lipid metabolite eicosenoate inhibits immune T-cell function by increasing mitochondrial ROS by inducing p53 transcription. Our results provide a new mechanism of metabolite regulation of effector T-cell function and provides a potential therapeutic target for restoring T-cell function during HIV infection.
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DOI：
10.1016/j.bbadis.2013.09.007
发表时间：
2014-08
影响因子：
6.2
作者：
Jin, Huajun;Kanthasamy, Arthi;Ghosh, Anamitra;Anantharam, Vellareddy;Kalyanaraman, Balaraman;Kanthasamy, Anumantha G.
通讯作者：
Kanthasamy, Anumantha G.
影响因子：
7.3
作者：
通讯作者：
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影响因子：
20.3
作者：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
通讯作者：
Jia, Wei
影响因子：
--
作者：
Mantzarlis K;Tsolaki V;Zakynthinos E
通讯作者：
Zakynthinos E
影响因子：
64.5
作者：
Buck MD;Sowell RT;Kaech SM;Pearce EL
通讯作者：
Pearce EL