An Approach to Reduce T Cell Infiltration into Atherosclerotic Plaques
While an atherosclerotic plaque initially emerges because too much cholesterol finds its way into one small portion of an artery wall, after a certain point that plaque increases in size by attracting attracting immune cells, stressing them into an inflammatory state, and ultimately killing them to add their mass to the plaque. This is not just the macrophages of the innate immune system, the cell type primarily responsible for attempting to clean up excess lipids and debris, but also T cells of the adaptive immune system. Like macrophages, T cells are attracted by the signaling associated with the inflammatory, damaged plaque environment, and promptly make the problem worse. Later still, there is a cancer-like phenomenon whereby surrounding smooth muscle cells multiply and enter the plaque, accelerating growth still further. That said, and as illustrated here, researchers are interested in trying to slow the development of plaque by reducing the attraction of immune cells to the plaque environment.
Atherosclerosis is the most common cause of life-threatening cardiovascular diseases. The disease involves chronic inflammation of the inner walls of blood vessels and within atherosclerotic plaques. For a long time, macrophages and foam cells were considered the principal agents in the formation of plaques. More recent studies, however, have focused on other immune system cells, CD8+ T cells, as it transpired that these are the immune cells most commonly found in human atherosclerotic plaques.
Scientists cultivated human atherosclerotic plaques together with CD8+ T cells from the same patient in a specially developed 3D tissue culture model. They discovered that the added CD8+ T cells were located primarily in the vicinity of newly formed blood vessels within the plaques. Further analyses using single-cell RNA sequencing and 3D microscopy revealed that the endothelial cells of these vessels express large amounts of the signaling protein CXCL12.
Following up on this discovery, the researchers investigated whether CXCL12 is involved in the recruitment of CD8+ cells by blocking the corresponding receptor (CXCR4) for this signaling protein in the T cells. "This did indeed lead to a significant reduction in CD8+ T cell migration into atherosclerosis plaques. These findings furnish new lines of approach for therapeutic strategies that could influence immune cell infiltration in atherosclerotic plaques."