Scientists study Regulatory T Cells and Cardiovascular Disease

Thanks to new study led by scientists at the La Jolla Institute for Immunology (LJI) and the Medical College of Georgia (MCG) at Augusta University, scientists can finally track down a dangerous type of human T cells.

Ex-T regulatory cells (exTregs) are immune cells that are infrequent in the body and, thus far, impossible to detect in human samples. The new work provides scientists with a dependable method for identifying human exTregs as well as insight into how exTregs contribute to inflammation and cardiovascular disease.

The researchers utilized fluorescent tags to identify exTregs in atherosclerotic mice. They subsequently found unique markers that distinguished these exTregs. They applied their findings to humans in order to detect exTregs in human blood.

“These cells are likely causing damage,” says LJI Postdoctoral Researcher Payel Roy, Ph.D., co-first author of the new Nature Immunology study. “Now we have the potential to use these biomarkers and screen for these cells in human blood.”

“Identifying exTregs in humans opens up more opportunities for research since patient material—like blood samples—are readily available,” adds study senior author Klaus Ley, M.D., co-director of MCG’s Immunology Center of Georgia.

Ex-T regulatory cells that are out of control

T cells perform numerous functions in the body. Some T cells are responsible for detecting danger and eliminating contaminated host cells. These are the warriors, the offensive lineup. T regulatory cells (Tregs) play a critical role in preventing other T cells from releasing too many inflammatory, or cytotoxic, chemicals during infection. The Tregs serve as referees.

Previous research by Ley and his LJI colleagues discovered that some T cells contribute to atherosclerosis by fighting a substance called apolipoprotein B (APOB), which is the main component of “bad” cholesterol that builds up in the arteries to form harmful plaques. As atherosclerosis progresses, these T cells intensify their attacks, perhaps contributing to artery inflammation. The interesting thing is that these T cells resemble the ordinarily beneficial Tregs.

The latest study exposes these cells’ true identities: They are former Republicans. Ex-Tregs resemble zombie Tregs. They’ve undergone genetic “deprogramming” and lost their ability to aid in inflammation regulation.

Scientists aren’t sure why exTregs emerge, but the phenomena could occur when the body fails to adjust to chronic disease.

“When you have too much chronic inflammation, say, for example, in heart disease, your body is highly stimulated and may be rewired to address the situation,” says LJI Postdoctoral Researcher Antoine Freuchet, Ph.D., who served as co-first author of the new study. “Because of that, this kind of Tregs, whose purpose was to keep the bad guys in check, turn bad themselves. Instead of controlling the inflammatory guys, they acquire inflammatory properties.”

Red Cell, Green Cell

The new study had to begin in mice. “ExTregs have been identified in mice for a long time, but there were no tools to find them in people,” says Ley. “In mice, you can use genetic manipulation to label cells, but you cannot do that in people.”

The researchers tagged both Tregs and potentially dangerous exTregs in a mouse model of atherosclerosis for the study. When Tregs were working regularly, these brilliant red and green tags glowed. A switch from green and red to solely red displayed real-time exTreg development.

The researchers then obtained organ samples from the mice and utilized flow cytometry to detect the green and red tags to separate the Tregs from the exTregs. To understand more about these cells, the researchers utilized a technique known as bulk RNA sequencing.

The sequencing revealed significant changes in gene expression and demonstrated that exTregs produce a separate set of genes that distinguishes them from Tregs. Finally, the scientist was able to identify specific exTreg indicators.

ExTreg detection in humans

The researchers then employed mouse exTreg markers to transfer them to single cell RNA sequencing on human blood samples. They were able to identify biomarkers for human exTregs using this method. Human blood samples were donated by researchers at the University of Virginia and the John and Susan Major Center for Clinical Investigation at LJI.

The researchers were ecstatic to discover that the exTreg indicators they’d discovered in mice samples were equally applicable to human exTregs. They discovered that exTregs from people with atherosclerosis may be more powerful.

“Now that we can detect exTregs in the blood, we can fish them out specifically and know who they are—know their molecular fingerprints,” says Roy.

The researchers intend to employ exTreg indicators in the future to detect and study the significance of these cells in other chronic health disorders, such as autoimmune disease patients. Roy and Freuchet are likewise interested in investigating samples taken over time from the same individual patients. ExTreg indicators may vary as atherosclerosis progresses. Would they see less exTregs if a patient was given an effective medication?

“This could be a powerful tool for future studies,” says Freuchet.

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