Key Points Mice with mTOR-deficient Treg develop a spontaneous severe autoimmune disease. mTOR expression is critical for Treg migration into nonlymphoid tissues. mTOR-deficient Treg have reduced stability. CD4+ Foxp3+ regulatory T cells (Treg) are essential to maintain immune tolerance, as their loss leads to a fatal autoimmune syndrome in mice and humans. Conflicting findings have been reported concerning their metabolism. Some reports found that Treg have low mechanistic target of rapamycin (mTOR) activity and would be less dependent on this kinase compared with conventional T cells, whereas other reports suggest quite the opposite. In this study, we revisited this question by using mice that have a specific deletion of mTOR in Treg. These mice spontaneously develop a severe and systemic inflammation. We show that mTOR expression by Treg is critical for their differentiation into effector Treg and their migration into nonlymphoid tissues. We also reveal that mTOR-deficient Treg have reduced stability. This loss of Foxp3 expression is associated with partial Foxp3 DNA remethylation, which may be due to an increased activity of the glutaminolysis pathway. Thus, our work shows that mTOR is crucial for Treg differentiation, migration, and identity and that drugs targeting this metabolism pathway will impact on their biology.

中文翻译：

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调节性 T 细胞稳定性和迁移取决于 mTOR

具有 mTOR 缺陷型 Treg 的小鼠会发展为自发性严重自身免疫性疾病。mTOR 表达对于 Treg 迁移到非淋巴组织至关重要。mTOR 缺陷的 Treg 稳定性降低。CD4+ Foxp3+ 调节性 T 细胞 (Treg) 对维持免疫耐受至关重要，因为它们的缺失会导致小鼠和人类发生致命的自身免疫综合征。已经报道了关于它们的代谢的相互矛盾的发现。一些报告发现 Treg 具有较低的雷帕霉素 (mTOR) 活性机制靶点，与传统 T 细胞相比，对这种激酶的依赖性较低，而其他报告则表明恰恰相反。在这项研究中，我们通过使用在 Treg 中具有特定 mTOR 缺失的小鼠重新审视了这个问题。这些小鼠自发地发生严重的全身炎症。我们表明，Treg 的 mTOR 表达对于它们分化为效应 Treg 和迁移到非淋巴组织至关重要。我们还揭示了 mTOR 缺陷型 Treg 的稳定性降低。Foxp3 表达的这种丧失与部分 Foxp3 DNA 重新甲基化有关，这可能是由于谷氨酰胺分解途径的活性增加。因此，我们的工作表明 mTOR 对 Treg 分化、迁移和身份识别至关重要，并且靶向该代谢途径的药物将影响其生物学。