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Updated: Sep 13, 2025
In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol
Published on: December 30, 2016
Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism
Wesley H Godfrey1, Judy J Lee1, Shruthi Shanmukha2
1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States.
Abstract:
The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3 PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-carbon metabolism, and epigenetic regulation of Treg differentiation and suppressive function.
Insights
Phosphoglycerate mutase (PGAM) regulates regulatory T cell (Treg) function by controlling serine synthesis. Inhibiting PGAM or serine metabolism impacts Treg differentiation and autoimmune disease, revealing new therapeutic targets.
Area of Science:
- Immunology
- Metabolic pathways
- Epigenetics
Background:
- Regulatory CD4 T cells (Tregs) are crucial for immune suppression and are influenced by metabolic alterations.
- Glycolytic enzymes play a role in Treg function, presenting potential therapeutic targets for immune modulation.
Purpose of the Study:
- To investigate the role of phosphoglycerate mutase (PGAM), a glycolytic enzyme, in Treg differentiation and function.
- To explore the link between PGAM, serine synthesis, one-carbon metabolism, and Treg-mediated immune suppression.
Main Methods:
- Investigated PGAM's role in Tregs using pharmacologic and genetic inhibition.
- Analyzed the impact of PGAM inhibition on Treg differentiation, suppressive function, and T helper 17 (Th17) markers.
- Examined the role of serine synthesis and one-carbon metabolism in Treg polarization.
- Utilized murine models of multiple sclerosis and autoimmune colitis to assess in vivo effects.
Main Results:
- PGAM was overexpressed in Tregs and associated with a highly suppressive phenotype.
- PGAM inhibition reduced Treg differentiation and suppressive function, promoting a Th17-like state.
- Serine synthesis from PGAM substrate (3-phosphoglycerate) was critical for Treg function; serine itself inhibited Treg polarization.
- Altering serine levels in vivo modulated peripheral Tregs and attenuated experimental autoimmune diseases.
- Inhibition of one-carbon metabolism enhanced Treg polarization and suppressive function in vitro and in vivo.
Conclusions:
- PGAM plays a novel regulatory role in Treg differentiation and function, linked to serine synthesis and one-carbon metabolism.
- Metabolic pathways including glycolysis, serine synthesis, and one-carbon metabolism are interconnected and influence Treg epigenetic regulation.
- Targeting PGAM and associated metabolic pathways offers a potential strategy for immune modulation in autoimmune diseases.
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