Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis.
Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis.
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DOI：
10.1038/s44161-023-00218-w
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发表时间：
2023-03
期刊：
影响因子：
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通讯作者：
Yin, Changjun
中科院分区：
文献类型：
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作者：
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;Yin, Changjun
动脉粥样硬化斑块在动脉内层形成，引发心脏病发作和中风。尽管已经在动脉粥样硬化中检测到T细胞，但耐受性功能障碍作为疾病驱动因素仍未被探索。在这里，我们通过单细胞RNA测序与T细胞抗原受体测序配对，研究了晚期动脉粥样硬化小鼠动脉粥样硬化斑块、动脉三级淋巴样器官和淋巴结的耐受性检查点。周围T细胞耐受性恶化的复杂模式在斑块中最为明显，其次是动脉三级淋巴样器官、淋巴结和血液。受影响的检查点包括CD4+、CD8+和调节性T细胞的克隆扩增；克隆扩增T细胞耐受调节转录物的异常；T细胞衰竭；Treg-TH17 T细胞转化；和功能失调抗原呈递。此外，人类斑块的单细胞rna测序图谱显示，小鼠斑块中观察到的CD8+ T细胞耐受功能障碍在人类冠状动脉和颈动脉斑块中是相同的。因此，我们的数据支持动脉粥样硬化作为一种真正的靶向动脉壁的T细胞自身免疫性疾病的概念。
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.