Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self.

Coronary artery disease — the buildup of plaque inside the arteries that supply the heart — has traditionally been thought of as a problem of fat and cholesterol clogging blood vessels. But scientists now understand there's more to the story: these plaques are also sites of chronic inflammation, packed with immune cells in various stages of activity. Figuring out exactly what these immune cells are doing could open the door to new treatments for a disease that currently has no cure. In this study, researchers used advanced single-cell technology to closely examine the immune cells found in human coronary artery plaques at different stages of development. This approach lets scientists study each individual cell's identity and behavior, rather than looking at tissue as one blended mixture. Alongside the immune cells called macrophages (which are already known to be involved in plaque buildup), the researchers found a surprisingly large number of T cells — a type of immune cell best known for fighting infections. Most of these T cells showed signs of being "memory" cells, meaning they had previously encountered and responded to a specific target. Strikingly, close to a third of them showed clear signs of active engagement through their T-cell receptors — the molecular sensors T cells use to recognize specific threats. Digging deeper, the researchers looked at the specific receptors on these activated T cells and found they had multiplied in number, a sign that they had been triggered to expand in response to something they recognized. Curiously, many of these T-cell receptors matched patterns typically seen responding to viruses like influenza and coronaviruses. However, those same viral patterns also closely resemble certain proteins naturally found on the surface of smooth muscle cells and blood vessel lining cells within the artery itself. This overlap raises an intriguing possibility: these T cells may not be responding to an actual viral infection at all, but rather mistakenly attacking the body's own artery wall cells because they resemble a virus, a form of autoimmune-like reaction. To understand what these confused, activated T cells might actually be doing inside the plaque, the researchers examined their gene activity in detail. Among the most highly activated T cells, two distinct groups showed patterns associated with inflammation and the ability to kill other cells. A third group produced a molecule called amphiregulin, which is known to encourage the overgrowth of smooth muscle cells and scarring — both processes that can make arterial plaques grow larger and more advanced. Altogether, this research suggests that T cells found in artery plaques aren't just innocent bystanders. They appear to have multiplied in response to a specific trigger, may be mistakenly reacting to the body's own tissue, and could be actively contributing to plaque growth by interacting with the surrounding artery cells. These insights point toward inflammation and possible autoimmune activity as important, and potentially treatable, drivers of coronary artery disease — insight that could eventually help guide new therapies targeting the immune system rather than just cholesterol.