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. A team led by Johan Duchêne and Remco Megens from the Institute for Cardiovascular Prevention (IPEK) has now identified a pathway involved in the recruitment of a certain subgroup of immune cells, known as CD8+ T cells, into plaques — with possible implications for new therapeutic approaches.

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 hematopoietic cells most commonly found in human atherosclerotic plaques. “To better understand their role, it’s important to know how they are recruited to the atherosclerotic plaques,” says Laura Parma, the first author of the study.

To answer this question, the 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,” affirms Duchêne, “suggesting that the CXCL12-CXCR4 signaling pathway plays a key role in this process.”

“These findings furnish new lines of approach for therapeutic strategies that could influence immune cell infiltration in atherosclerotic plaques and could contribute in the long term to the development of new treatment options for cardiovascular diseases” concludes Megens.