Vitamin C emerges as an unexpected guardian against autoimmunity

For centuries, vitamin C has been synonymous with scurvy, the devastating disease that once plagued sailors deprived of fresh fruits and vegetables. While the cure for scurvy — eating the right foods — was well known, it wasn’t until the 1900s that scientists discovered that vitamin C was what prevented the disease. Today, researchers are still finding unexpected roles for the essential nutrient.

Yongqiang Feng, PhD, Department of Immunology, discovered one of those hidden roles while studying the seemingly unrelated problem of how the immune system prevents certain T cells from turning against the body’s own tissues. T-cells need to recognize proteins as self or non-self, to respond to and attack only the non-self proteins. When that process fails, the result can be autoimmunity, contributing to diseases ranging from lupus to diabetes to neurodegeneration. 

Most autoreactive T cells are eliminated during development in the thymus, and many of the rest are converted into regulatory T cells that suppress harmful immune responses. But a smaller group of cells escapes both safeguards and becomes conventional T cells, which still do not usually trigger autoimmune disease. Feng’s lab wanted to find out why.

“We did not understand how this remaining population of autoreactive T cells, called conventional T cells, stopped themselves from causing autoimmune conditions,” Feng said. “When we looked at which genes were critical to that self-inhibition, we were surprised to find the vitamin C transporter played a central role.”

Through previous work, Feng suspected that nutrient sensing was involved in T-cell tolerance, the processes the body uses to deal with autoreactive T cells. So, his lab removed nutrient-related genes from T cells using a CRISPR screen. Published in Science Advances, they unexpectedly identified the gene Slc23a2, the vitamin C (ascorbate) transporter, as essential to T-cell development and immunity.

“In the past, the function of vitamin C in T cells was overshadowed because scurvy is so devastating,” corresponding author Feng said. “When we selectively deleted the transporter in T cells, we could observe its effect on autoimmunity directly.” T cells without the transporter were more differentiated than those with it, including conventional T cells that reacted to self-antigens, producing low-grade persistent inflammation in mouse models.

Connecting vitamin C to immuno-aging

At first, the relevance was unclear, as the vitamin C transporter functions properly in most humans. However, the risks of autoimmune diseases and excess inflammation are known to increase with age. Therefore, Feng’s group compared vitamin C levels in immune cells from young mice and humans to older mice and humans. They found that cells from older groups contained substantially lower intracellular vitamin C than younger ones, with decreases of up to 40%.

“Cells lose vitamin C transportation over aging, which we think is one of the reasons why cells get old,” Feng explained. “As a result, those cells actually become more autoreactive, with a constant release of subclinical inflammatory signaling proteins called cytokines in a process we are calling immuno-aging.”

That chronic, low-level inflammation has already been linked to a wide range of aging-related conditions. One of these is neurodegeneration, where T cells inappropriately inflame the brain and cause damage, contributing to cognitive decline that can be difficult or impossible to reverse. The discovery gives a potential path to address such aging-related problems promoted by autoimmunity, as restoring vitamin C concentrations within immune cells during aging could theoretically prevent such issues. However, that research is still in its infancy.

“We currently do not have the ability to raise the amount of vitamin C in these cells to therapeutic levels,” Feng clarified. “We want to find a way to do so, but we are still in the early stages of understanding this process.”

Vitamin C’s epigenetic activity

To better understand how vitamin C protects against autoimmunity and potentially uncover drug targets, the scientists looked at how vitamin C controlled gene expression in T cells. They found that it controlled the molecular mechanisms that regulate gene activity without changing the underlying DNA sequence (epigenetics). One major form of epigenetic control is DNA methylation, in which small chemical tags are added to DNA to suppress gene expression. Feng’s team found that vitamin C strongly affected this system through TET proteins, a family of enzymes that help remove those repressive marks and shape T-cell activation and differentiation.

When the researchers removed the TET genes and compared the overlap in DNA methylation changes to those that occur from removing the vitamin C receptor, the overlap was striking. The two disruptions produced similar epigenetic changes and autoimmunity in mice.

“We showed that TET proteins had a high reliance on vitamin C,” Feng explained. “Without it, TET proteins have a severe defect in catalyzing DNA demethylation, leading to genes being activated that should remain repressed, which then leads to a failure of self-inhibition and an increase in autoimmune attack by these T cells.”

Together, the findings present a model of T-cell tolerance with vitamin C at its center. In younger, well-nourished immune cells, vitamin C enters through its transporter and supports TET-mediated regulation that keeps potentially self-reactive T cells in check. With aging, reduced transport appears to lower intracellular vitamin C, weakening that restraint and allowing persistent inflammation to emerge.

Further investigating vitamin C in immunity

Moving forward, Feng’s lab is researching how and where this process is happening in other immune cells and continuing to look for ways to alter it.

“We’ve found that vitamin C, which has been studied for over a century, is an essential ingredient to tune T cell activity,” Feng said. “We are now trying to extend this fundamental finding to other immune cell types, to see if we can further understand and harness this process to prevent immuno-aging and potential downstream immune-mediated diseases.”

The findings highlight how even a molecule as familiar as vitamin C can still have undiscovered roles in biology. What was once considered a guardian for sailors’ health at sea by preventing scurvy may  lead to discoveries that provide new strategies that will, in a similar way, prevent inflammation-driven and autoimmune diseases before they take hold.