Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.
Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.
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多胺代谢影响HIV感染者口腔粘膜中的T细胞功能障碍
DOI：
10.1038/s41467-023-36163-2
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发表时间：
2023-01-25
影响因子：
16.6
通讯作者：
Pandiyan, P.
中科院分区：
文献类型：
--
作者：
Mahalingam, S. S.;Jayaraman, S.;Bhaskaran, N.;Schneider, E.;Faddoul, F.;da Silva, A. Paes;Lederman, M. M.;Asaad, R.;Adkins-Travis, K.;Shriver, L. P.;Pandiyan, P.
免疫细胞的代谢变化有助于免疫反应的生理和病理生理结果。在这里，通过比较未感染和HIV+个体的蛋白质表达、转录组和唾液代谢组谱，我们发现HIV+患者口腔黏膜中的多胺代谢存在扰动。体外人扁桃体类器官感染模型的机制研究表明，HIV感染T细胞也导致多胺合成增加，这依赖于caspase-1、IL-1β和鸟氨酸脱羧酶-1的活性。HIV-1还导致多胺合成中间体（包括鸟氨酸脱羧酶-1）的表达升高，以及功能失调调节性T细胞(tregys)/T辅助细胞17 （Th17）细胞比例升高。阻断caspase-1和多胺合成中间体逆转tregys表型，显示多胺途径在HIV-1感染期间改变T细胞功能中的直接作用。最后，口腔黏膜tregys /Th17比值和CD4超激活与唾液腐胺水平呈正相关，在HIV+患者唾液中发现唾液腐胺水平升高。因此，通过揭示HIV感染期间异常增加的多胺合成的作用，我们的研究揭示了慢性病毒感染可以驱动不同的T细胞效应程序和Treg功能障碍的机制。多胺代谢是辅助T细胞极化的决定因素。在这里，Mahalingam等人分析了HIV感染者口腔黏膜的代谢和转录组学特征，以证明HIV-1感染期间多胺合成对T细胞功能障碍的影响。
Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction. Polyamine metabolism is a determinant of T helper cell polarization. Here, Mahalingam et al analyse the metabolic and transcriptomic profile of oral mucosa from people living with HIV to demonstrate the effect of polyamine synthesis on T cell dysfunction during HIV-1 infection.
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