TY - JOUR
T1 - MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function
AU - Sugiura, Ayaka
AU - Andrejeva, Gabriela
AU - Voss, Kelsey
AU - Heintzman, Darren R.
AU - Xu, Xincheng
AU - Madden, Matthew Z.
AU - Ye, Xiang
AU - Beier, Katherine L.
AU - Chowdhury, Nowrin U.
AU - Wolf, Melissa M.
AU - Young, Arissa C.
AU - Greenwood, Dalton L.
AU - Sewell, Allison E.
AU - Shahi, Shailesh K.
AU - Freedman, Samantha N.
AU - Cameron, Alanna M.
AU - Foerch, Patrik
AU - Bourne, Tim
AU - Garcia-Canaveras, Juan C.
AU - Karijolich, John
AU - Newcomb, Dawn C.
AU - Mangalam, Ashutosh K.
AU - Rabinowitz, Joshua D.
AU - Rathmell, Jeffrey C.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/1/11
Y1 - 2022/1/11
N2 - 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.
AB - 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.
KW - CD4 T cells
KW - CRISPR screen
KW - MTHFD2
KW - T cell differentiation
KW - inflammation
KW - mTORC1
KW - metabolic checkpoint
KW - methylation
KW - one carbon metabolism
KW - purine metabolism
UR - http://www.scopus.com/inward/record.url?scp=85122250678&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122250678&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2021.10.011
DO - 10.1016/j.immuni.2021.10.011
M3 - Article
C2 - 34767747
AN - SCOPUS:85122250678
SN - 1074-7613
VL - 55
SP - 65-81.e9
JO - Immunity
JF - Immunity
IS - 1
ER -