RT Journal Article
SR Electronic
T1 MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.03.428939
DO 10.1101/2021.02.03.428939
A1 Ayaka Sugiura
A1 Gabriela Andrejeva
A1 Kelsey Voss
A1 Darren R. Heintzman
A1 Katherine L. Beier
A1 Melissa M. Wolf
A1 Dalton Greenwood
A1 Xiang Ye
A1 Shailesh K. Shahi
A1 Samantha N. Freedman
A1 Alanna M. Cameron
A1 Patrik Foerch
A1 Tim Bourne
A1 Xincheng Xu
A1 Juan C. Garcia-Canaveras
A1 Ashutosh K. Mangalam
A1 Joshua D. Rabinowitz
A1 Jeffrey C. Rathmell
YR 2021
UL http://biorxiv.org/content/early/2021/02/03/2021.02.03.428939.abstract
AB 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.