More than twenty years ago, a research group identified a specific type of T cell in humans that plays a role in suppressing the immune system. This discovery led to the understanding that regulatory T cells, when not functioning properly, contribute to autoimmune diseases like multiple sclerosis (MS). For an extended period, the exact reasons for this dysfunction remained unknown. However, recent research has uncovered that an increase in a protein called PRDM1-S, which is crucial for immune responses, triggers this loss of immune regulation. This process involves a complex interplay between various genetic and environmental factors, including high levels of salt intake. These new insights also highlight a potential target for treatments aimed at a broad range of autoimmune conditions.
Over twenty years ago, a team led by David Hafler, who was a Harvard researcher at that time, found a type of T cell in humans that suppresses the immune response. This led to the discovery that when these regulatory T cells (Tregs) are defective, they are a significant factor in the development of autoimmune diseases such as multiple sclerosis (MS). Yet, the precise mechanisms behind this issue remained elusive for years.
In a recent study spearheaded by Yale researchers, it was revealed that the decline in immune regulation is linked to elevated levels of PRDM1-S, a protein tied to immune functions. This increase is associated with a complex interaction of various genetic and environmental elements, prominently including high salt consumption.
The research, featured in the journal Science Translational Medicine, also indicates a new potential target for universal treatments for autoimmune diseases in humans.
The study was led by Tomokazu Sumida, an assistant professor at Yale School of Medicine, alongside Hafler, who holds the William S. and Lois Stiles Edgerly Professorship in Neurology and serves as a professor of immunobiology at Yale.
Hafler remarked, “These experiments uncover a crucial underlying mechanism related to the loss of immune regulation in MS and potentially other autoimmune conditions. Additionally, they provide deeper understanding into the mechanisms behind Treg dysfunction in human autoimmune diseases.”
Autoimmune diseases represent some of the most prevalent disorders among young adults, influenced by both genetic and environmental considerations such as a deficiency in vitamin D and fatty acids. In earlier research, Sumida and Hafler indicated that elevated salt levels also play a part in the onset of multiple sclerosis, which affects the central nervous system. They noted that high salt levels can provoke inflammation in CD4 T cells, while simultaneously impairing the function of regulatory T cells, a disruption mediated by an enzyme critical for cell signaling known as SGK-1.
In this latest study, the researchers utilized RNA sequencing to analyze gene expression between MS patients and healthy individuals. They found that in MS patients, the gene PRDM1-S, also known as BLIMP-1, which is vital for immune regulation, showed increased expression.
Interestingly, the rise in PRDM1-S led to heightened expression of the salt-sensitive SGK-1 enzyme, resulting in the disruption of regulatory T cell functions. The researchers also discovered a similar overexpression of PRDM1-S in other autoimmune diseases, indicating it may be a shared characteristic of Treg dysfunction.
Sumida stated, “With these findings, we are working on developing medications that can specifically target and reduce the expression of PRDM1-S in regulatory T cells. We are also collaborating with other researchers at Yale to apply innovative computational methods aimed at enhancing the function of regulatory T cells, creating new strategies to treat various autoimmune diseases.”
The study was conducted alongside Bradley Bernstein and Manolis Kellis, long-term collaborators of Hafler from the Broad Institute of MIT and Harvard, as well as several other research organizations.
Additional researchers from the Yale team include neurologist Matthew R. Lincoln and research assistants Alice Yi, Helen Stillwell, and Greta Leissa.
