Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, Esch-sur-Alzette, Luxembourg.
Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig; Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
Cell Metab. 2020 May 5;31(5):920-936.e7. doi: 10.1016/j.cmet.2020.03.004. Epub 2020 Mar 25.
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
调节性 T 细胞 (Treg) 维持免疫稳态，防止自身免疫。丝氨酸刺激谷胱甘肽 (GSH) 的合成，并进入一碳代谢网络 (1CMet)，这对效应 T 细胞 (Teff) 的反应至关重要。然而，丝氨酸在 Treg 中的功能、与 GSH 的联系以及在应激反应中的作用尚不清楚。在这里，我们使用 Treg 特异性敲除谷氨酸半胱氨酸连接酶催化亚基 (Gclc) 的小鼠表明，Treg 中 GSH 的丧失改变了丝氨酸的摄取和合成，而这种反馈回路的完整性对于 Treg 的抑制能力至关重要。尽管 Gclc 缺失不会损害 Treg 的分化，但突变小鼠表现出严重的自身免疫和增强的抗肿瘤反应。缺乏 Gclc 的 Treg 显示出增加的丝氨酸代谢、mTOR 激活和增殖，但 FoxP3 下调。体外和体内限制细胞丝氨酸可恢复 Gclc 缺陷型 Treg 的 FoxP3 表达和抑制能力。我们的工作揭示了 GSH 在限制丝氨酸可用性以维持 Treg 功能方面的意外作用。
