TY - JOUR T1 - MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function JF - bioRxiv DO - 10.1101/2021.02.03.428939 SP - 2021.02.03.428939 AU - Ayaka Sugiura AU - Gabriela Andrejeva AU - Kelsey Voss AU - Darren R. Heintzman AU - Katherine L. Beier AU - Melissa M. Wolf AU - Dalton Greenwood AU - Xiang Ye AU - Shailesh K. Shahi AU - Samantha N. Freedman AU - Alanna M. Cameron AU - Patrik Foerch AU - Tim Bourne AU - Xincheng Xu AU - Juan C. Garcia-Canaveras AU - Ashutosh K. Mangalam AU - Joshua D. Rabinowitz AU - Jeffrey C. Rathmell Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/03/2021.02.03.428939.abstract N2 - Antigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.Competing Interest StatementJCR has held stock equity in Sitryx and within the past two years has received unrelated research support, travel, and honorarium from Sitryx, Caribou, Nirogy, Kadmon, Calithera, Tempest, Merck, Mitobridge, and Pfizer. AMC, PF, and TB are employees of Sitryx. ER -