単細胞RNA解析とT細胞抗原受容体プロファイリングの組み合わせにより、動脈硬化症におけるT細胞寛容のチェックポイントの破綻が示される Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis
Zhihua Wang,Xi Zhang,Shu Lu,Chuankai Zhang,Zhe Ma,Rui Su,Yuanfang Li,Ting Sun,Yutao Li,Mingyang Hong,Xinyi Deng,Mohammad Rafiee Monjezi,Michael Hristov,Sabine Steffens,Donato Santovito,Klaus Dornmair,Klaus Ley,Christian Weber,Sarajo K. Mohanta,Andreas J. R. Habenicht & Changjun Yin
Nature Cardiovascular Research Published:23 February 2023
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.