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

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 KarijolichDawn C. Newcomb, Ashutosh K. Mangalam, Joshua D. Rabinowitz, Jeffrey C. Rathmell

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)65-81.e9
Issue number1
StatePublished - Jan 11 2022

All Science Journal Classification (ASJC) codes

  • Infectious Diseases
  • Immunology and Allergy
  • Immunology


  • CD4 T cells
  • CRISPR screen
  • MTHFD2
  • T cell differentiation
  • inflammation
  • mTORC1
  • metabolic checkpoint
  • methylation
  • one carbon metabolism
  • purine metabolism


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