2021年11月11日，《免疫》杂志在线发表了美国科学家的一项最新研究成果。来自范德比尔特大学的Jeffrey C. Rathmell研究组发现，MTHFD2是控制效应和调节T细胞命运和功能的一个代谢检查点。

研究人员表明，一碳（1C）代谢酶亚甲基四氢叶酸脱氢酶2（MTHFD2）调节活化T细胞的新嘌呤合成和信号传导，从而促进增殖和炎症细胞因子的产生。在致病的T辅助17（Th17）细胞中，MTHFD2防止了转录因子FoxP3的异常上调，同时不适当地获得抑制能力。MTHFD2的缺乏也促进了调节性T（Treg）细胞的分化。从机制上讲，MTHFD2的抑制导致了嘌呤库的耗竭、嘌呤生物合成中间体的积累和营养传感器mTORC1信号的减少。MTHFD2对调节Th17细胞的DNA和组蛋白甲基化也至关重要。

重要的是，MTHFD2的缺乏降低了多种体内炎症疾病模型的疾病严重程度。因此，MTHFD2是一个整合嘌呤代谢和致病效应细胞信号的代谢检查点，也是1C代谢途径中的一个潜在治疗靶标。

据悉，抗原刺激可促进T细胞代谢的重新规划，从而满足生物合成、生物能量和信号传递的需求。

附：英文原文

Title: MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function

Author: Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R. Heintzman, Xincheng Xu, Matthew Z. Madden, Xiang Ye, Katherine L. Beier, Nowrin U. Chowdhury, Melissa M. Wolf, Arissa C. Young, Dalton L. Greenwood, Allison E. Sewell, Shailesh K. Shahi, Samantha N. Freedman, Alanna M. Cameron, Patrik Foerch, Tim Bourne, Juan C. Garcia-Canaveras, John Karijolich, Dawn C. Newcomb, Ashutosh K. Mangalam, Joshua D. Rabinowitz, Jeffrey C. Rathmell

Issue&Volume: 2021-11-11

Abstract: Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic,bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzymemethylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation andinflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 preventedaberrant upregulation of the transcription factor FoxP3 along with inappropriate gainof suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) celldifferentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools,accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purinemetabolism with pathogenic effector cell signaling and is a potential therapeutictarget within 1C metabolism pathways.

DOI: 10.1016/j.immuni.2021.10.011

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00448-9