Vitamin C Fosters the In Vivo Differentiation of Peripheral CD4+ Foxp3− T Cells into CD4+ Foxp3+ Regulatory T Cells but Impairs Their Ability to Prolong Skin Allograft Survival

Abstract

Regulatory T cells (Tregs) are critical players of immunological tolerance due to their ability to suppress effector T cell function thereby preventing transplant rejection and autoimmune diseases. During allograft transplantation, increases of both Treg expansion and generation, as well as their stable function, are needed to ensure allograft acceptance; thus, efforts have been made to discover new molecules that enhance Treg-mediated tolerance and to uncover their mechanisms. Recently, vitamin C (VitC), known to regulate T cell maturation and dendritic cell-mediated T cell polarization, has gained attention as a relevant epigenetic remodeler able to enhance and stabilize the expression of the Treg master regulator gene Foxp3, positively affecting the generation of induced Tregs (iTregs). In this study, we measured VitC transporter (SVCT2) expression in different immune cell populations, finding Tregs as one of the cell subset with the highest levels of SVCT2 expression. Unexpectedly, we found that VitC treatment reduces the ability of natural Tregs to suppress effector T cell proliferation in vitro, while having an enhancer effect on TGFβ-induced Foxp3+ Tregs. On the other hand, VitC increases iTregs generation in vitro and in vivo, however, no allograft tolerance was achieved in animals orally treated with VitC. Lastly, Tregs isolated from the draining lymph nodes of VitC-treated and transplanted mice also showed impaired suppression capacity ex vivo. Our results indicate that VitC promotes the generation and expansion of Tregs, without exhibiting CD4+ T cell-mediated allograft tolerance. These observations highlight the relevance of the nutritional status of patients when immune regulation is needed.

A comparative view on vitamin C effects on αβ- versus γδ T-cell activation and differentiation

“…When naive T cells were transferred into T‐cell deficient (RAG‐KO) mice with an allogeneic skin transplant and VitC was applied orally in combination, once again FoxP3 + T cells were found in higher numbers. However, this had no positive impact on the skin‐graft survival …”

The Impact of Dietary Components on Regulatory T Cells and Disease

“…A recent study by Oyarce et al showed that tTreg cells pretreated with vitamin C before coculturing with effector CD4 + T cells did not enhanced Treg ability to suppress T cell proliferation regardless of their increased FOXP3 expression. By contrast, in vitro-induced iTregs generated in presence of vitamin C showed improved suppressive capacities (144).…”

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

“…Oyarce et al. and others showed in mice that, whereas vitamin C did not affect tTreg suppressive capacity, it greatly enhanced the function in pTregs both in vitro and in vivo [32]. It is intriguing to speculate that this difference may be due to distinct modes of metabolic control in tTregs versus pTregs, an issue that needs to be further clarified.…”