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

TitleMTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.
Publication TypeJournal Article
Year of Publication2022
AuthorsSugiura, 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, García-Cañaveras, JC, Karijolich, J, Newcomb, DC, Mangalam, AK, Rabinowitz, JD, Rathmell, JC
JournalImmunity
Volume55
Issue1
Pagination65-81.e9
Date Published2022 Jan 11
ISSN1097-4180
KeywordsAnimals, Cell Differentiation, Cytokines, Disease Models, Animal, DNA Methylation, Humans, Inflammation, Inflammation Mediators, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Methylenetetrahydrofolate Dehydrogenase (NADP), Mice, Mice, Transgenic, Mutation, Purines, Signal Transduction, T-Lymphocytes, Regulatory, Th17 Cells
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>

DOI10.1016/j.immuni.2021.10.011
Alternate JournalImmunity
PubMed ID34767747
PubMed Central IDPMC8755618
Grant ListS10 OD023475 / OD / NIH HHS / United States
R01 DK105550 / DK / NIDDK NIH HHS / United States
T32 DK101003 / DK / NIDDK NIH HHS / United States
F30 CA239367 / CA / NCI NIH HHS / United States
T32 GM007347 / GM / NIGMS NIH HHS / United States
P30 CA068485 / CA / NCI NIH HHS / United States
R01 HL136664 / HL / NHLBI NIH HHS / United States
R01 CA217987 / CA / NCI NIH HHS / United States
R01 AI137075 / AI / NIAID NIH HHS / United States
P30 CA086862 / CA / NCI NIH HHS / United States
R01 AI153167 / AI / NIAID NIH HHS / United States