Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.
Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.
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DOI：
10.1038/ni.3269
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发表时间：
2015-11
影响因子：
30.5
通讯作者：
Matarese G
中科院分区：
文献类型：
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作者：
De Rosa V;Galgani M;Porcellini A;Colamatteo A;Santopaolo M;Zuchegna C;Romano A;De Simone S;Procaccini C;La Rocca C;Carrieri PB;Maniscalco GT;Salvetti M;Buscarinu MC;Franzese A;Mozzillo E;La Cava A;Matarese G
人类调节性T细胞(Treg细胞)由传统的T细胞(Tconv细胞)经T细胞抗原受体(TCR)(诱导的Treg细胞)次优刺激后发展而来，表达转录因子Foxp3，具有抑制作用，并表现出活跃的增殖和代谢状态。在这里，我们发现iTreg细胞的诱导和抑制功能密切依赖于糖酵解，糖酵解通过糖酵解酶-1控制含有外显子2的Foxp3剪接变异体(Foxp3-E2)。在包括多发性硬化症和1型糖尿病在内的人类自身免疫性疾病中，iTreg细胞的Foxp3-E2相关的抑制活性发生了改变，并与糖酵解和通过白细胞介素2的信号转导受损有关。这种糖酵解与Foxp3-E2变异之间的联系通过烯醇化酶-1显示了一个先前未知的机制来控制健康和自身免疫中Treg细胞的诱导和功能。
Human regulatory T cells (Treg cells) that develop from conventional T cells (Tconv cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced Treg cells (iTreg cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iTreg cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2–related suppressive activity of iTreg cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of Treg cells in health and in autoimmunity.