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Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4+ T Cell Effector Functions and Activation-Induced Metabolic Reprogramming
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-07-08 , DOI: 10.4049/jimmunol.2000137
Stefanie Y Tan 1 , Yogeshwar Kelkar 1 , Angela Hadjipanayis 1 , Arun Shipstone 1 , Thomas A Wynn 1 , J Perry Hall 2
Affiliation  

Key Points Metformin + 2-DG represses human CD4+ T cell IFN-γ production and cell proliferation. Metformin + 2-DG inhibits human CD4+ T cell Gln uptake and metabolic reprogramming. Metformin + 2-DG reduces MYC and HIF-1A expression in human CD4+ T cells. Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation–induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4+ T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.

中文翻译:

二甲双胍和 2-脱氧葡萄糖协同抑制人类 CD4+ T 细胞效应功能和激活诱导的代谢重编程

要点二甲双胍 + 2-DG 抑制人 CD4+ T 细胞 IFN-γ 的产生和细胞增殖。二甲双胍 + 2-DG 抑制人 CD4+ T 细胞 Gln 摄取和代谢重编程。二甲双胍 + 2-DG 降低人 CD4+ T 细胞中 MYC 和 HIF-1A 的表达。代谢重编程在 T 细胞活化和分化中起着核心作用,抑制活化 T 细胞中的关键代谢途径代表了开发治疗自身免疫性疾病的新治疗剂的合乎逻辑的方法。广泛使用的抗糖尿病药物二甲双胍和糖酵解抑制剂 2-脱氧葡萄糖 (2-DG) 已分别用于研究小鼠免疫细胞中氧化磷酸化和糖酵解的抑制作用。已发表的研究表明,与单独使用二甲双胍或 2-DG 治疗相比,二甲双胍和 2-DG 联合治疗可有效抑制小鼠 T 细胞活化诱导的效应过程。在这项研究中,我们报告说,二甲双胍 + 2-DG 治疗比单独使用二甲双胍或 2-DG 治疗更有效地抑制了活化的原代人类 CD4+ T 细胞中 IFN-γ 的产生和细胞增殖。二甲双胍 + 2-DG 对人类 T 细胞的影响伴随着激活诱导的代谢转录程序的显着重塑,部分原因是关键转录调节因子 MYC 和 HIF-1A 的抑制。因此,二甲双胍 + 2-DG 治疗显着抑制了 MYC 依赖性代谢基因和过程,但发现这种作用与 mTORC1 信号无关。
更新日期:2020-07-08
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