@article{4316,
  keywords = {Animals, Disease Models, Animal, Mice, Humans, Signal Transduction, Mutation, Mice, Transgenic, Cell Differentiation, Inflammation, DNA Methylation, Cytokines, Mechanistic Target of Rapamycin Complex 1, Lymphocyte Activation, Methylenetetrahydrofolate Dehydrogenase (NADP), Purines, Inflammation Mediators, T-Lymphocytes, Regulatory, Th17 Cells},
  author = {Ayaka Sugiura and Gabriela Andrejeva and Kelsey Voss and Darren Heintzman and Xincheng Xu and Matthew Madden and Xiang Ye and Katherine Beier and Nowrin Chowdhury and Melissa Wolf and Arissa Young and Dalton Greenwood and Allison Sewell and Shailesh Shahi and Samantha Freedman and Alanna Cameron and Patrik Foerch and Tim Bourne and Juan Garc{\'\i}a-Ca{\~n}averas and John Karijolich and Dawn Newcomb and Ashutosh Mangalam and Joshua Rabinowitz and Jeffrey Rathmell},
  title = {MTHFD2 is a metabolic checkpoint controlling effector and regulatory T~cell fate and function.},
  abstract = { <p>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.</p> },
  year = {2022},
  journal = {Immunity},
  volume = {55},
  pages = {65-81.e9},
  month = {2022 Jan 11},
  issn = {1097-4180},
  doi = {10.1016/j.immuni.2021.10.011},
  language = {eng},
}