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

• Published in: Immunity (Cambridge, Mass.) Vol. 55; no. 1; pp. 65 - 81.e9
• Main Authors: Sugiura, Ayaka, Andrejeva, Gabriela, Voss, Kelsey, Heintzman, Darren R., Xu, Xincheng, Madden, Matthew Z., Ye, Xiang, Beier, Katherine L., Chowdhury, Nowrin U., Wolf, Melissa M., Young, Arissa C., Greenwood, Dalton L., Sewell, Allison E., Shahi, Shailesh K., Freedman, Samantha N., Cameron, Alanna M., Foerch, Patrik, Bourne, Tim, Garcia-Canaveras, Juan C., Karijolich, John, Newcomb, Dawn C., Mangalam, Ashutosh K., Rabinowitz, Joshua D., Rathmell, Jeffrey C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.01.2022
• Subjects: Animals; CD4+ T cells; Cell Differentiation; CRISPR screen; Cytokines - metabolism; Disease Models, Animal; DNA Methylation; Humans; inflammation; Inflammation - immunology; Inflammation Mediators - metabolism; Lymphocyte Activation; Mechanistic Target of Rapamycin Complex 1 - metabolism; metabolic checkpoint; methylation; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism; Mice; Mice, Transgenic; MTHFD2; mTORC1; Mutation - genetics; one carbon metabolism; purine metabolism; Purines - biosynthesis; Signal Transduction; T cell differentiation; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; one carbon metabolism; CD4+ T cells; purine metabolism; MTHFD2; inflammation; T cell differentiation; methylation; metabolic checkpoint; CRISPR screen; mTORC1; CD4(+) T cells
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2021.10.011

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. [Display omitted] •MTHFD2 is critical for activated CD4 T cells to maintain de novo purine synthesis•Insufficient MTHFD2 promotes Treg cell-like phenotypes and metabolism in Th17 cells•Inhibition of MTHFD2 suppresses mTORC1 signaling and alters histone methylation•MTHFD2 can be targeted to protect against inflammation and autoimmunity in vivo Nucleotide synthesis is required to support rapid T cell proliferation. Sugiura et al. show that de novo purine metabolism signals direct T cell differentiation and function and identify MTHFD2 as a metabolic checkpoint and therapeutic target for inflammatory diseases.