Researchers identify mechanisms of dysfunctional Tregs in MS
Protein increase triggers reaction, study finds
Researchers uncovered a mechanism by which regulatory T-cells (Tregs), immune cells that keep the immune system in check and prevent its overactivity, become dysfunctional in people with multiple sclerosis (MS) and other autoimmune conditions.
Tregs from MS patients exhibited increased levels of a protein called PRDM1-S that ultimately caused destabilization of FOXP3, an important Treg protein. A similar mechanism seemed to be at play in other autoimmune conditions.
“These experiments reveal a key underlying mechanism for the loss of immune regulation in MS and likely other autoimmune diseases,” David Hafler, MD, the study’s senior author and professor of neurology and immunobiology at Yale School of Medicine, said in a university news story. “They also add mechanistic insight into how Treg dysfunction occurs in human autoimmune diseases.”
The study, “An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction,” was published in Science Translational Medicine.
Regulatory T-cells are an important class of immune cells that work to regulate other immune cells and make sure they don’t become too active. They are critical for immune tolerance, the process by which the immune system learns not to attack the body’s own healthy tissues. If this process fails, autoimmunity can arise.
Tregs and autoimmune attacks
Hafler discovered the role of Tregs more than 20 years ago, and later determined that their dysfunction is implicated in the autoimmune attacks that cause nervous system damage in MS. Tregs have been a focus of MS research and treatment development, though the molecular mechanisms underlying their dysfunction in the autoimmune context haven’t been fully understood.
In a previous study, Hafler and colleagues showed that high levels of salt may contribute to MS development. Salt, they found, induced inflammation by activating pro-inflammatory immune T-cells and causing a loss of Treg function. That process was determined to be mediated by a salt-sensitive enzyme called SGK-1.
In the latest study, the researchers aimed to further explore the possible mechanisms of Treg dysfunction in autoimmunity by looking at gene activity in Tregs from MS patients relative to healthy people.
They found that Tregs from MS patients had increased activity of a gene called primate-specific transcription factor (PRDM1-S), which produces a transcription factor protein of the same name. Transcription factors are proteins that influence gene activity, and PRDM1-S plays a key role in regulating the activity of genes involved in immune function.
This increase in PRDM1-S activity, which indicates higher production of the PRDM1-S protein, led to increases in SGK1 gene activity. That in turn led to a destabilization of FOXP3, the master transcription factor of Tregs, regulating their maturation and function. Moreover, Tregs became dysfunctional.
In other experiments, the researchers determined that this PRDM1-S-mediated Treg dysfunction was shared among other autoimmune diseases, indicating it could be a common feature of Treg dysfunction.
Further analyses of Tregs from MS patients identified other transcription factors that appeared to also be involved in the identified molecular circuit.
Knowing how Treg dysfunction arises in autoimmune disease opens doors for the development of new treatments.
“Based on these insights, we are now developing drugs that can target and decrease [activity] of PRDM1-S in regulatory T cells,” said Tomokazu Sumida, MD, PhD, the study’s first author and an assistant professor at Yale. “And we have initiated collaborations with other Yale researchers using novel computational methods to increase the function of regulatory T cells to develop new approaches that will work across human autoimmune diseases.”
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