Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments.
Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments.
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DOI：
10.1016/j.cmet.2016.12.018
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发表时间：
2017-06-06
期刊：
影响因子：
29
通讯作者：
Beier UH
中科院分区：
文献类型：
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作者：
Angelin A;Gil-de-Gómez L;Dahiya S;Jiao J;Guo L;Levine MH;Wang Z;Quinn WJ 3rd;Kopinski PK;Wang L;Akimova T;Liu Y;Bhatti TR;Han R;Laskin BL;Baur JA;Blair IA;Wallace DC;Hancock WW;Beier UH
免疫细胞在不同的代谢环境中发挥作用。具有低葡萄糖和高乳酸盐浓度的组织，例如肠道或缺血组织，通常需要免疫应答以更亲耐受，避免针对自身抗原或肠道细菌的不必要的反应。调节性T细胞（Treg）维持外周耐受，但Treg在富含乳酸的低葡萄糖环境中如何发挥作用尚不清楚。我们报道Treg转录因子Foxp 3通过抑制Myc和糖酵解，增强氧化磷酸化和增加烟酰胺腺嘌呤二核苷酸氧化来重编程T细胞代谢。这些适应允许Treg在低葡萄糖、富含乳酸的环境中具有代谢优势;抵抗乳酸介导的T细胞功能和增殖的抑制。这种代谢表型可能解释了TGFAP如何在组织损伤期间促进外周免疫耐受，以及癌细胞如何在肿瘤微环境中逃避免疫破坏。因此，了解Treg代谢可能会导致癌症和自身免疫性疾病中选择性免疫调节的新方法。
Immune cells function in diverse metabolic environments. Tissues with low glucose and high lactate concentrations, such as the intestinal tract or ischemic tissues, frequently require immune responses to be more pro-tolerant avoiding unwanted reactions against self-antigens or commensal bacteria. T-regulatory cells (Treg) maintain peripheral tolerance, but how Treg function in low glucose lactate rich environments is unknown. We report that the Treg transcription factor Foxp3 reprograms T cell metabolism by suppressing Myc and glycolysis, enhancing oxidative phosphorylation, and increasing nicotinamide adenine dinucleotide oxidation. These adaptations allow Treg a metabolic advantage in low glucose, lactate rich environments; resisting lactate mediated suppression of T cell function and proliferation. This metabolic phenotype may explain how Tregs promote peripheral immune tolerance during tissue injury, but also how cancer cells evade immune destruction in the tumor microenvironment. Understanding Treg metabolism may therefore lead to novel approaches for selective immune modulation in cancer and autoimmune diseases.