Mice are not men: scRNA-sequencing of the human atherosclerotic plaque identifies species-specific immune cell phenotypes that associate with clinical disease

Local and systemic immunity shapes atherosclerosis, the most frequent cause of cardiovascular disease. The distinct function of immune cells has been mostly defined by preclinical mouse studies, while recent immune cell atlases of human atherosclerosis suggest divergent immune cell mechanisms. Until now, it is not clear whether genetic animal models replicate the immunological complexity of human disease. Here we demonstrate significant variations in the immune cell composition in murine and human atherosclerotic plaques by integrative single-cell RNA-sequencing. In contrast to widely applied mouse models, human plaque leukocytes primarily contained various T-cell phenotypes displaying activation, memory formation, and pro-inflammatory signaling. In a clinical validation cohort, the abundance of activated T cell clusters in human plaques associated with the extend of clinical disease emphasizing the specific role of T-cell-driven immunity in plaque development and instability. Collectively, our study questions the translatability of mouse models for studying the immune system in atherosclerosis.