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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sugiura, A; Andrejeva, G; Voss, K; Heintzman, DR; Xu, X; Madden, MZ; Ye, X; Beier, KL; Chowdhury, NU; Wolf, MM; Young, AC; Greenwood, DL; Sewell, AE; Shahi, SK; Freedman, SN; Cameron, AM; Foerch, P; Bourne, T; Garcia-Canaveras, JC; Karijolich, J; Newcomb, DC; Mangalam, AK; Rabinowitz, JD; Rathmell, JC

Published Date

  • January 11, 2022

Published In

Volume / Issue

  • 55 / 1

Start / End Page

  • 65 - 81.e9

PubMed ID

  • 34767747

Pubmed Central ID

  • PMC8755618

Electronic International Standard Serial Number (EISSN)

  • 1097-4180

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2021.10.011


  • eng

Conference Location

  • United States