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One carbon (metabolism) to rule T cell identity

Nature Reviews Immunology volume 21, page 206 (2021)Cite this article

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T cells need to respond promptly and efficiently to antigenic challenge and must profoundly alter their metabolism when doing so. Although much progress has been made in understanding the use of energy-producing metabolic pathways (such as glycolysis and the tricarboxylic acid cycle) in T cell activation, there has been less focus on crucial biosynthetic pathways for cell proliferation and growth. One-carbon (1C) metabolism encompasses a set of metabolic pathways that interconvert single carbon moieties to control purine synthesis, redox balance, DNA methylation and other synthetic processes. T cells are known to depend on serine, a key source of 1C units, for proliferation and effector function, but the details of 1C metabolism in T cells are poorly understood.

In this preprint (non-peer-reviewed), Sugiura et al. set out to address the impacts of 1C metabolism on T cell activation and function. Using a 1C-targeting CRISPR library screen, the authors found several enzymes to be crucial for T cell proliferation upon in vivo antigen challenge. Of these, only methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a key enzyme for mitochondrial purine production, was specifically transcriptionally upregulated across multiple human autoimmune diseases. Pharmacological inhibition and genetic deletion of MTHFD2 significantly impaired T cell proliferation and activation. Intriguingly, lack of MTHFD2 activity led to sustained expression of the transcription factor FOXP3 in differentiated T helper 17 (TH17) cells and regulatory T (Treg) cells, which increased their capacity to suppress CD8+ T cells. Mechanistically, MTHFD2 inhibition in TH1 cells and Treg cells resulted in accumulation of the purine intermediate AICA ribonucleotide, which can suppress mTOR activity and thus impair biosynthetic pathways. By contrast, TH17 cells with MTHFD2 inhibition showed no alterations in mTOR activity, but markedly increased DNA trimethylation and HIF1α expression, which drives their differentiation. These phenotypes were rescued by formate supplementation, which directly supplies 1C units. Pharmacological inhibition of MTHFD2 in vivo decreased pathology in mouse models of multiple sclerosis.

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  1. OxMS Preprint Journal Club, Kennedy Institute of Rheumatology, Oxford, UK

    Felix Clemens Richter & Alexander J. Clarke

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  1. Felix Clemens Richter
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  2. Alexander J. Clarke
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Correspondence to Felix Clemens Richter.

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Richter, F.C., Clarke, A.J. One carbon (metabolism) to rule T cell identity. Nat Rev Immunol 21, 206 (2021). https://doi.org/10.1038/s41577-021-00530-1

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  • DOI: https://doi.org/10.1038/s41577-021-00530-1

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