Vitamin C2026

Increased phenotypic and functional stability of human allospecific induced Tregs is associated with Vitamin C-mediated TSDR demethylation.

Alvarez-Salazar Evelyn K, Reyes-Barrientos Judith E, Cortés-Hernández Arimelek, Saint-Martin Castellanos Abril et al. — Frontiers in immunology

Summary

This study reveals that Vitamin C can significantly improve the stability and function of specific immune cells called regulatory T cells (Tregs) when grown in a lab. These cells are crucial for preventing the immune system from overreacting, which is vital for conditions like organ transplantation or autoimmune diseases. The findings suggest that adding Vitamin C could make cell-based therapies more effective by ensuring these therapeutic cells remain stable and potent.

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Key points

Vitamin C helps stabilize specific immune cells called regulatory T cells (Tregs) that are grown in the lab.
Stable Tregs are better at controlling unwanted immune responses, which is important for conditions like organ rejection.
This stability is linked to Vitamin C influencing how genes are regulated, specifically through a process called demethylation.
These findings could lead to improved cell therapies for conditions requiring immune tolerance, such as organ transplantation.

What the study looked at

What question did the study ask? Researchers wanted to find out if Vitamin C could help make lab-grown regulatory T cells (iTregs) more stable and effective. These cells are important for calming the immune system, but they often lose their stability when used in therapies, limiting their potential for treating inflammatory diseases or preventing organ rejection. How was it studied? The team generated human iTregs in the lab and then grew them with or without added Vitamin C. They then observed how these cells developed, how stable their characteristics were, and how well they could suppress other immune cells. They also looked at genetic changes, specifically how Vitamin C affected gene regulation through a process called demethylation. What did it find? The study found that iTregs treated with Vitamin C were significantly more stable, maintained their ability to suppress immune responses, and resisted inflammatory conditions better. This enhanced stability was linked to Vitamin C's role in reducing methylation in a key gene region (FOXP3 TSDR), which helps maintain the cells' identity and function.

Dietary takeaway

While this research focuses on advanced cell therapies, it reinforces the broader importance of adequate Vitamin C intake for overall immune health. Consuming a variety of Vitamin C-rich foods, such as citrus fruits, berries, bell peppers, and leafy greens, supports your body's natural defenses. Remember, this is one laboratory study, and more research is needed to fully understand the implications for human health and dietary recommendations.

Abstract

INTRODUCTION: While numerous preclinical models emphasize the therapeutic promise of -induced Tregs (iTregs) for managing inflammatory diseases and promoting tolerance, their translation to clinical use is limited by concerns over phenotypic and functional instability, largely due to an epigenetic profile distinct from thymic Tregs. METHODS: To address this, we generated and expanded iTregs in the presence of Vitamin C, known to activate TET enzymes that demethylate critical gene regions such as FOXP3. Antigen-specific Tregs were derived from allogeneic co-cultures of monocyte-derived dendritic cells and naïve T cells. After 7 days, allo-Tregs were isolated by FACS and further expanded for 3 weeks with IL-2, TGF-β, rapamycin, with or without Vitamin C supplementation. RESULTS: iTregs treated with Vitamin C displayed heightened FOXP3 expression and sustained high levels of suppressive markers (PD-L1, CD39, TIGIT, and CTLA-4), as well as chemokine receptors linked to allograft homing (CCR4, CCR5, and CXCR3). These cells also demonstrated enhanced allospecific suppression of CD4 and CD8 T cell proliferation, even in the presence of pro-inflammatory cytokines. Notably, this proinflammatory milieu did not trigger the production of intracellular cytokines IL-17 and IFN-γ by allo-iTregs, confirming their sustained phenotypic and functional stability. Advanced analysis demonstrated that allo-iTregs possess a unique profile, setting them apart from conventional T cells. Pyrosequencing of the FOXP3 TSDR revealed reduced CpG methylation in Vitamin C-treated iTregs (60.9% at day 21 and 43.5% at day 28) compared to untreated allo-iTregs (85.9% at day 21 and 80.5% at day 28) and naïve T cells (92.8%). In addition, transcriptomic analysis demonstrated that the core Treg transcriptional signature remained largely intact with Vitamin C treatment, irrespective of cytokine exposure, whereas the major transcriptional changes were associated with activation, proliferation, and cell cycle regulation. DISCUSSION: In summary, Vitamin C enhances both the phenotypic and functional stability of allospecific iTregs, even under proinflammatory conditions, correlating with increased TSDR demethylation, while preserving the transcription of key Treg genes. These results suggest that Vitamin C-treated allospecific iTregs are superior candidates for immunotherapy strategies to promote long-term tolerance in transplant recipients.

View on PubMed →DOI: 10.3389/fimmu.2026.1827886