Aggravating atherosclerosis

Study of T cells sheds light on cardiovascular events

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NEW YORK—Mount Sinai Health System researchers say they have demonstrated for the first time that atherosclerotic plaque, the fatty buildup in arteries that can cause heart attack and stroke, contains a high number of T cells. The research, which was published in the October 7 issue of Nature Medicine, could offer new insight on ischemic cardiovascular events, explain how the immune system contributes to cardiovascular disease and complications and aid in developing new treatments to prevent those cardiovascular events.
An important part of the immune system, T cells help to protect the body from infection and cancer, but they may also aggravate atherosclerosis. The Mount Sinai researchers performed a deep single-cell analysis of immune cells in plaque, which reportedly had never been done before in humans.
According to the paper in Nature Medicine, “Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke).”
“This is a first study towards the ultimate goal of building a single-cell immune atlas of human atherosclerosis. By profiling individual cells in blood and atherosclerotic plaques, we found new inflammatory alterations in plaques related to cardiovascular events,” explained lead investigator Dr. Chiara Giannarelli, an assistant professor of medicine (cardiology) and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai. “We found that T cells, a cell type known to fight infections and cancer, may have an unanticipated important role in driving atherosclerotic cardiovascular disease. Exploring the diversity of T cells in human atherosclerosis may lead to new therapeutics in the future.”
The researchers studied 46 male and female patients undergoing carotid artery surgery at the Mount Sinai Hospital. Forty percent of the patients, whose average age was 72, had recently had a stroke. To analyze atherosclerotic plaque removed during the surgery and the patients’ blood immune cells, the researchers used a combination of CyTOF, single-cell RNA sequencing and CITE-seq to look at the individual protein and gene expression of single cells. They found an abundance of T cells and an increased infiltration of a subset of pro-inflammatory T cells called CD4+ in patients who had suffered a recent stroke.
The researchers said that plaques from symptomatic patients were “characterized by a distinct subset of CD4+ T cells and by T cells that were activated and differentiated.” Some T cell subsets in these plaques showed markers of T cell exhaustion. Macrophages from these plaques had alternatively activated phenotypes, “including subsets associated with plaque vulnerability.” In plaques from patients who were asymptomatic, T cells and macrophages that were activated displayed evidence of interleukin-1β signaling.
Other subsets of T cells, including CD8+ T cells, were infiltrating plaques by being highly active or inflammatory, differentiated and highly specialized to the plaque environment, or exhausted and not killing disease cells. The exhausted T cells expressed PD-1, a protein that usually prevents T cells from killing other cells. CD8+ T-cells usually recognize and kill cancer cells or cells infected by viruses. All of these cell subsets could increase plaque inflammation in stroke patients, possibly putting these patients at a higher risk of future cardiac events.
“These findings suggest that PD-1 inhibitors, a breakthrough treatment that is used in cancer to turn T-cells against the tumor, may also activate exhausted T-cells in plaque,” noted Giannarelli . “This could increase plaque inflammation and possibly the risk for cardiovascular events in patients.”
Co-author Dr. Miriam Merad, director of the Precision Immunology Institute and director of the Human Immune Monitoring Center at the Icahn School of Medicine, described the study as “a perfect example of how single-cell mapping of human disease lesions can transform our understanding of disease pathophysiology,” adding that it “generated a new hypothesis about disease drivers that we hope will lead to novel therapies.”
Dr. Michelle Olive, program officer at the National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences, concluded that the research “shows the molecular connections linking blood and cellular make-up of the atherosclerotic plaque within the same individual and the clinical outcome” and demonstrates “that cutting-edge techniques like CyTOF and other single-cell technologies are useful in charting the landscape of atherosclerotic plaques.”

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