Glutathione restricts serine metabolism to preserve regulatory T cell function Original paper

What was studied?

This study examined how glutathione controls regulatory T cell function by limiting serine metabolism and maintaining immune balance. The authors focused on the intracellular antioxidant glutathione and its role beyond redox control, especially its influence on metabolic signaling pathways that regulate FoxP3 expression and suppressive capacity in regulatory T cells. Using genetic, metabolic, and functional approaches, the study investigated how loss of glutathione synthesis alters serine uptake, one-carbon metabolism, mTOR activation, and immune homeostasis. The work aimed to define a mechanistic link between redox state and nutrient metabolism in regulatory T cells and to explain how metabolic dysregulation leads to autoimmunity and altered tumor immunity.

Who was studied?

The study primarily used mouse models with regulatory T cell–specific deletion of the glutamate cysteine ligase catalytic subunit, the key enzyme required for glutathione synthesis. Male and female mice were analyzed to assess immune outcomes, survival, inflammation, and tumor growth. The authors also studied isolated mouse regulatory T cells and conventional T cells in vitro to assess metabolic flux, cytokine production, and suppressive capacity. To support clinical relevance, the study included experiments using human regulatory T cells derived from healthy donor peripheral blood, allowing confirmation that the glutathione–serine regulatory mechanism operates in human immune cells.

Most important findings

The study showed that glutathione loss in regulatory T cells caused excessive serine uptake and synthesis, which activated mTOR signaling and reduced FoxP3 expression. This metabolic shift increased cell proliferation but impaired suppressive function. Glutathione-deficient regulatory T cells failed to control effector T cell activation, leading to severe IFN-γ–driven autoimmunity in mice. Restricting serine availability, blocking serine transport, or inhibiting mTOR restored FoxP3 expression and regulatory function. In tumor models, impaired regulatory T cell suppression enhanced anti-tumor immunity, resulting in slower tumor growth. The findings establish glutathione as a metabolic checkpoint that preserves regulatory T cell identity by limiting serine-driven metabolic activation rather than acting solely as an antioxidant.

Greatest implications

This study identifies glutathione as a critical regulator of immune tolerance through its control of serine metabolism and mTOR signaling in regulatory T cells. For clinicians, the findings highlight how metabolic imbalance, rather than immune cell loss, can drive autoimmune disease. The work suggests that dietary or pharmacologic modulation of serine metabolism, redox balance, or mTOR activity could restore regulatory T cell function in autoimmune and inflammatory conditions. At the same time, controlled disruption of this pathway may enhance anti-tumor immunity. The study provides a clear mechanistic framework linking redox biology, metabolism, and immune regulation that may guide future immunometabolic therapies.