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 - Funding Information:
J.C.R. is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics; a scientific advisory board member and stockholder of Caribou Biosciences; a member of the scientific advisory board of Nirogy Therapeutics; has consulted for Merck, Pfizer, and Mitobridge within the past 3 years; and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. J.D.R. is a co-founder and stockholder in Raze Therapeutics, Toran, Serien Therapeutics, and Farber Partners and an advisor and stockholder in Agios Pharmaceuticals, Kadmon Pharmaceuticals, Bantam Pharmaceuticals, Colorado Research Partners, Rafael Holdings, the Barer Institute, and L.E.A.F. Pharmaceuticals; he has received consulting fees and research funding from Pfizer and Rafael and is the inventor of patents held by Princeton University. A.M.C., P.F., and T.B. are employees of Sitryx Therapeutics.
Funding Information:
We thank members of the Rathmell lab for contributing to this project. We thank Thomas Aune for providing RNA-seq data and J. Cools (VIB) for providing the pMx-U6-gRNA-GFP construct. We thank Max R. Van Belkum for designing the MTHFD2 qPCR primers. We thank Nello Mainolfi, Vipin Suri, Adam Friedman, and Mark Manfredi from Raze Therapeutics, Inc. (Boston, MA) for providing the Raze 1459 compound, which was used to corroborate findings (data not shown). Diagrams were created with BioRender. We acknowledge the Translational Pathology Shared Resource, supported by NCI/NIH Cancer Center support grant 5P30 CA68485-19 and shared instrumentation grant S10 OD023475-01A1, for the Leica Bond RX. This work was supported by the William E. Paul Distinguished Innovator Award for the Lupus Research Alliance (to J.C.R.), R01s DK105550 (to J.C.R.), HL136664 (to J.C.R. and D.C.N.), CA217987 (to J.C.R.), AI153167 (to J.C.R.), AI137075 (to A.K.M.), T32 DK101003 (K.V.), and T32 GM007347 (to A.S.). A.S. G.A. and J.C.R. designed the research. A.S. G.A. K.V. D.R.H. X.X. M.Z.M. X.Y. K.L.B. N.C. M.M.W. A.C.Y. D.L.G. A.E.S. S.K.S. S.N.F. A.M.C. P.F. T.B. and J.C.G.-C. performed the research. A.S. G.A. X.Y. J.K. D.C.N. A.K.M. J.D.R. and J.C.R. analyzed data. A.S. and J.C.R. wrote the paper with contributions from the other authors. J.C.R. is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics; a scientific advisory board member and stockholder of Caribou Biosciences; a member of the scientific advisory board of Nirogy Therapeutics; has consulted for Merck, Pfizer, and Mitobridge within the past 3 years; and has received research support from Incyte Corp. Calithera Biosciences, and Tempest Therapeutics. J.D.R. is a co-founder and stockholder in Raze Therapeutics, Toran, Serien Therapeutics, and Farber Partners and an advisor and stockholder in Agios Pharmaceuticals, Kadmon Pharmaceuticals, Bantam Pharmaceuticals, Colorado Research Partners, Rafael Holdings, the Barer Institute, and L.E.A.F. Pharmaceuticals; he has received consulting fees and research funding from Pfizer and Rafael and is the inventor of patents held by Princeton University. A.M.C. P.F. and T.B. are employees of Sitryx Therapeutics. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.
Funding Information:
We thank members of the Rathmell lab for contributing to this project. We thank Thomas Aune for providing RNA-seq data and J. Cools (VIB) for providing the pMx-U6-gRNA-GFP construct. We thank Max R. Van Belkum for designing the MTHFD2 qPCR primers. We thank Nello Mainolfi, Vipin Suri, Adam Friedman, and Mark Manfredi from Raze Therapeutics, Inc. (Boston, MA) for providing the Raze 1459 compound, which was used to corroborate findings (data not shown). Diagrams were created with BioRender. We acknowledge the Translational Pathology Shared Resource, supported by NCI/NIH Cancer Center support grant 5P30 CA68485-19 and shared instrumentation grant S10 OD023475-01A1 , for the Leica Bond RX. This work was supported by the William E. Paul Distinguished Innovator Award for the Lupus Research Alliance (to J.C.R.), R01s DK105550 (to J.C.R.), HL136664 (to J.C.R. and D.C.N.), CA217987 (to J.C.R.), AI153167 (to J.C.R.), AI137075 (to A.K.M.), T32 DK101003 (K.V.), and T32 GM007347 (to A.S.).
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 -