Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis

Wang, Zhihua; Zhang, Xi; Lu, Shu; Zhang, Chuankai; Ma, Zhe; Su, Rui; Li, Yuanfang; Sun, Ting; Li, Yutao; Hong, Mingyang; Deng, Xinyi; Monjezi, Mohammad Rafiee; Hristov, Michael; Steffens, Sabine; Santovito, Donato; Dornmair, Klaus; Ley, Klaus; Weber, Christian; Mohanta, Sarajo K.; Habenicht, Andreas J. R. und Yin, Changjun (2023): Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis. In: Nature Cardiovascular Research, Bd. 2, Nr. 3: 290-+

Abstract

Atherosclerotic plaques form in the inner layer of arteries triggering heart attacks and strokes. Although T cells have been detected in atherosclerosis, tolerance dysfunction as a disease driver remains unexplored. Here we examine tolerance checkpoints in atherosclerotic plaques, artery tertiary lymphoid organs and lymph nodes in mice burdened by advanced atherosclerosis, via single-cell RNA sequencing paired with T cell antigen receptor sequencing. Complex patterns of deteriorating peripheral T cell tolerance were observed being most pronounced in plaques followed by artery tertiary lymphoid organs, lymph nodes and blood. Affected checkpoints included clonal expansion of CD4+, CD8+ and regulatory T cells;aberrant tolerance-regulating transcripts of clonally expanded T cells;T cell exhaustion;Treg-TH17 T cell conversion;and dysfunctional antigen presentation. Moreover, single-cell RNA-sequencing profiles of human plaques revealed that the CD8+ T cell tolerance dysfunction observed in mouse plaques was shared in human coronary and carotid artery plaques. Thus, our data support the concept of atherosclerosis as a bona fide T cell autoimmune disease targeting the arterial wall. Wang et al. profiled T cells in atherosclerotic plaques, artery tertiary lymphoid organs, and lymph nodes in mice with advanced atherosclerosis by single-cell RNA sequencing paired with T cell antigen receptor sequencing and observed complex patterns of deteriorating peripheral T cell tolerance. Signs of CD8+ tolerance dysfunction were found also in human plaques transcriptomic data, indicating that atherosclerosis can be considered as a bona fide T cell autoimmune disease.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198