Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Chemistry, Ludwig Cancer Research Institute Princeton Branch, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Immunity. 2022 Jan 11;55(1):65-81.e9. doi: 10.1016/j.immuni.2021.10.011. Epub 2021 Nov 11.
Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.
抗原刺激促进 T 细胞代谢重编程，以满足增加的生物合成、生物能量和信号需求。我们表明，一碳（1C）代谢酶亚甲基四氢叶酸脱氢酶 2（MTHFD2）调节活化 T 细胞中的从头嘌呤合成和信号转导，以促进增殖和炎性细胞因子的产生。在致病性 T 辅助 17（Th17）细胞中，MTHFD2 防止转录因子 FoxP3 的异常上调以及抑制能力的不当获得。MTHFD2 缺乏也促进了调节性 T（Treg）细胞的分化。在机制上，MTHFD2 抑制导致嘌呤池耗竭、嘌呤生物合成中间产物积累和营养传感器 mTORC1 信号降低。MTHFD2 对于调节 Th17 细胞中的 DNA 和组蛋白甲基化也很关键。重要的是，MTHFD2 缺乏可降低多种体内炎症性疾病模型的疾病严重程度。因此，MTHFD2 是一个代谢检查点，可将嘌呤代谢与致病性效应细胞信号转导整合在一起，是 1C 代谢途径中的一个潜在治疗靶点。
