MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function
Sugiura et al. (BioRxiv) DOI: 10.1101/2021.02.03.428939
One carbon metabolism
Sugiura et al. investigated the role of one carbon (1C) metabolism in T cell fate and phenotype. Using a combination of a 1C-targeting CRISPR library and RNA sequencing datasets, the authors identify MTHFD2, a mitochondrial protein involved in the folate cycle, to be an interesting enzyme induced during inflammatory pathologies and T cells activation. Pharmacological inhibition (using several inhibitors) and genetic deletion showed that MTHFD2 is crucial for T cell proliferation and pro-inflammatory Th17 expansion and function. Loss of MTHFD2 increases Foxp3 and suppressive potential in both Tregs and Th17 cells suggesting that this pathway is differentially regulated in pro-inflammatory and anti-inflammatory T cells after activation. Mechanistically, pharmacological loss of MTHFD2 could be rescued using formate supplementation. In Th1 and Treg cells, the loss of MTHFD2 appears to impact mTORC-mediated biosynthesis pathways, while Th17 show an MTHFD2-dependent control of the transcription factor HIF1a. The authors suggest that this may be connected to increased DNA trimethylation. These findings may be of interest to autoimmune diseases marked by strong Th17 responses, as demonstrated by the authors in the EAE model.
Strong use of pharmacological agents to inhibit MTHFD2 (while on-target effects may be clear, possible off-target effects especially on MTHFD1 may not be entirely excluded); therefore, stronger use of their genetic CD4-Cre driven KO system would be advantageous (e.g. for the EAE model at the end)
Direct link between HIF1a expression and DNA methylation is not fully established
From an intestinal immunological perspective: In the intestine, Foxp3+ RORgt+ Tregs exist and it would be of interest to know whether these intestinal Treg subsets are using 1C metabolism in different ways (potentially through microbiotic substrates)
Disease relevance may need further establishing since an overall loss of immune cells in the EAE model was observed which could be due to MTHFD2 loss may impair further immune cell proliferation (e.g. other T cells than Th17, and myeloid cells)
The preprint shows an interesting differential use of 1C metabolism between different T cell subsets. The specific induction of MTHFD2 makes it an interesting drug target for future more translatable studies. The study adds crucial data to the understanding of how 1C metabolism can control T cell responses as similarly observed by serine deprivation (Ma et al. 2017).
The data is of importance to several fields of immunology and (on the long-run) for translational science. Several auto-inflammatory pathologies show a specific upregulation of MTHFD2 and targeting this enzyme may indeed become a viable treatment option, after further translational investigation. In our opinion, this study is of interest to the field of immunometabolism and T cell research.
Reviewed by Felix C Richter as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow him on Twitter.