Regulatory T cells (Tregs) are a subset of T cells that function to maintain homeostasis and prevent autoimmunity. Tregs can be applied in the treatment of autoimmune diseases and in the prevention of transplant rejection and graft vs. host disease (GvHD). Researchers have been working to generate stable induced Tregs (iTregs) for treating autoimmune diseases and rejection to transplanted organs. Now, researchers at La Jolla Institute for Immunology (LJI) and Emory University School of Medicine report that vitamin C and TET proteins can be combined to give Tregs their life-saving power.

Their findings are published in the journal EMBO Reports in a paper titled, “Whole-genome analysis of TET dioxygenase function in regulatory T cells.”

“TET methylcytosine dioxygenases are essential for the stability and function of regulatory T cells, which maintain immune homeostasis and self-tolerance and express the lineage-determining transcription factor Foxp3,” wrote the researchers. “Here, we use whole-genome analyses to show that the transcriptional program and epigenetic features (DNA modification, chromatin accessibility) of Treg cells are attenuated in the absence of Tet2 and Tet3.”

“Vitamin C can be used to stabilize iTregs generated in vitro,” explained LJI instructor Xiaojing Yue, PhD. “We hope that these kinds of induced Tregs can be used in the future for treatment of autoimmune diseases and organ transplantation.”

The current study, led by LJI professor Anjana Rao, PhD, and Emory instructor Benjamin G. Barwick, PhD, builds on the previous finding that vitamin C can enhance the enzymatic activity of TET proteins and prompt the generation of stable iTregs under lab conditions.

The researchers wanted to first analyze the gene expression patterns and other key epigenetic features of the induced Tregs. “We wanted to study the entire system at a whole genome level using next-generation sequencing technology to better understand the molecular features of these cells,” said Yue.

The researchers observed that a major type of epigenetic modification involves the DNA itself through the addition or removal of methyl groups from cytosines. The methyl groups can be further oxidized by TET enzymes. All of these interactions can eventually change how cells “read” the DNA code. They also observed the alteration of DNA accessibility: whether DNA is loosely or tightly coiled. As the DNA coils unwind, regulatory regions become exposed which subsequently influence gene expression.

“In mice that are deficient for components of IL-2/STAT5 signaling, such as IL-2, IL-2 receptors, or STAT5, the Tregs cannot develop properly or they can have impaired function,” Yue said.

“We are looking for more small molecules to stabilize TET activity and generate induced Tregs that are even more stable,” added Yue. “These induced Tregs could eventually be used to treat patients.”

The researchers believe this new combination will lead to scientists thinking about new ways in which they approach treating autoimmune diseases.

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