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

Publication ,  Journal Article
Sugiura, A; Andrejeva, G; Voss, K; Heintzman, DR; Xu, X; Madden, MZ; Ye, X; Beier, KL; Chowdhury, NU; Wolf, MM; Young, AC; Greenwood, DL ...
Published in: Immunity
January 2022

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.

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Published In

Immunity

DOI

EISSN

1097-4180

ISSN

1074-7613

Publication Date

January 2022

Volume

55

Issue

1

Start / End Page

65 / 81.e9

Related Subject Headings

  • Th17 Cells
  • T-Lymphocytes, Regulatory
  • Signal Transduction
  • Purines
  • Mutation
  • Mice, Transgenic
  • Mice
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Mechanistic Target of Rapamycin Complex 1
  • Lymphocyte Activation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sugiura, A., Andrejeva, G., Voss, K., Heintzman, D. R., Xu, X., Madden, M. Z., … Rathmell, J. C. (2022). MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function. Immunity, 55(1), 65-81.e9. https://doi.org/10.1016/j.immuni.2021.10.011
Sugiura, Ayaka, Gabriela Andrejeva, Kelsey Voss, Darren R. Heintzman, Xincheng Xu, Matthew Z. Madden, Xiang Ye, et al. “MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.Immunity 55, no. 1 (January 2022): 65-81.e9. https://doi.org/10.1016/j.immuni.2021.10.011.
Sugiura A, Andrejeva G, Voss K, Heintzman DR, Xu X, Madden MZ, et al. MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function. Immunity. 2022 Jan;55(1):65-81.e9.
Sugiura, Ayaka, et al. “MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.Immunity, vol. 55, no. 1, Jan. 2022, pp. 65-81.e9. Epmc, doi:10.1016/j.immuni.2021.10.011.
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. MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function. Immunity. 2022 Jan;55(1):65-81.e9.
Journal cover image

Published In

Immunity

DOI

EISSN

1097-4180

ISSN

1074-7613

Publication Date

January 2022

Volume

55

Issue

1

Start / End Page

65 / 81.e9

Related Subject Headings

  • Th17 Cells
  • T-Lymphocytes, Regulatory
  • Signal Transduction
  • Purines
  • Mutation
  • Mice, Transgenic
  • Mice
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Mechanistic Target of Rapamycin Complex 1
  • Lymphocyte Activation