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MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R. Heintzman, Katherine L. Beier, Melissa M. Wolf, Dalton Greenwood, Xiang Ye, Shailesh K. Shahi, Samantha N. Freedman, Alanna M. Cameron, Patrik Foerch, Tim Bourne, Xincheng Xu, Juan C. Garcia-Canaveras, Ashutosh K. Mangalam, Joshua D. Rabinowitz, Jeffrey C. Rathmell
doi: https://doi.org/10.1101/2021.02.03.428939
Ayaka Sugiura
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Gabriela Andrejeva
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Kelsey Voss
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Darren R. Heintzman
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Katherine L. Beier
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Melissa M. Wolf
2Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Dalton Greenwood
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Xiang Ye
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Shailesh K. Shahi
3Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
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Samantha N. Freedman
3Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
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Alanna M. Cameron
4Sitryx Therapeutics Limited, Magdalen Centre, Oxford Science Park, Oxford, UK
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Patrik Foerch
4Sitryx Therapeutics Limited, Magdalen Centre, Oxford Science Park, Oxford, UK
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Tim Bourne
4Sitryx Therapeutics Limited, Magdalen Centre, Oxford Science Park, Oxford, UK
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Xincheng Xu
5Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544
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Juan C. Garcia-Canaveras
5Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544
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Ashutosh K. Mangalam
3Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
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Joshua D. Rabinowitz
5Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544
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Jeffrey C. Rathmell
1Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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  • For correspondence: jeff.rathmell@vumc.org
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SUMMARY

Antigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.

Competing Interest Statement

JCR has held stock equity in Sitryx and within the past two years has received unrelated research support, travel, and honorarium from Sitryx, Caribou, Nirogy, Kadmon, Calithera, Tempest, Merck, Mitobridge, and Pfizer. AMC, PF, and TB are employees of Sitryx.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function
Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R. Heintzman, Katherine L. Beier, Melissa M. Wolf, Dalton Greenwood, Xiang Ye, Shailesh K. Shahi, Samantha N. Freedman, Alanna M. Cameron, Patrik Foerch, Tim Bourne, Xincheng Xu, Juan C. Garcia-Canaveras, Ashutosh K. Mangalam, Joshua D. Rabinowitz, Jeffrey C. Rathmell
bioRxiv 2021.02.03.428939; doi: https://doi.org/10.1101/2021.02.03.428939
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MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function
Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R. Heintzman, Katherine L. Beier, Melissa M. Wolf, Dalton Greenwood, Xiang Ye, Shailesh K. Shahi, Samantha N. Freedman, Alanna M. Cameron, Patrik Foerch, Tim Bourne, Xincheng Xu, Juan C. Garcia-Canaveras, Ashutosh K. Mangalam, Joshua D. Rabinowitz, Jeffrey C. Rathmell
bioRxiv 2021.02.03.428939; doi: https://doi.org/10.1101/2021.02.03.428939

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