Aims The distinct functions of immune cells in atherosclerosis have been mostly defined by pre-clinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression are only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches. Methods and results Single-cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programmes of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leucocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor, and pro-inflammatory signalling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-colour flow cytometry associated with the extent of clinical atherosclerosis. Conclusion Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis—a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-)immunity in human plaque formation and instability.

中文翻译：

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跨物种单细胞 RNA 测序揭示了人颈动脉和实验性小鼠动脉粥样硬化中适应性免疫的不同表型和激活状态


目的 免疫细胞在动脉粥样硬化中的独特功能主要由临床前小鼠研究确定。相比之下，人们对人动脉粥样硬化斑块的免疫细胞组成及其对疾病进展的贡献知之甚少。目前仍不确定遗传动物模型是否允许有价值的转化方法。方法和结果 进行单细胞 RNA 测序 （scRNA-seq） 以确定人颈动脉粥样硬化斑块中的免疫细胞景观。人类免疫细胞库表现出出乎意料的高异质性，并且以 T 细胞谱系的细胞为主，免疫组化证实了这一发现。与来自外膜和动脉粥样硬化血管组织的 7 个小鼠 scRNA-seq 数据集的生物信息学整合揭示了总共 51 种细胞类型和分化状态的身份，其中一些在物种之间仅很差，并且仅在人类中发现。小鼠模型中免疫细胞的位置、频率和转录程序与人颈动脉粥样硬化中的免疫细胞景观不同。与动脉粥样硬化的标准小鼠模型相比，人类斑块白细胞以几种 T 细胞表型为主，具有 T 细胞活化和记忆形成、T 细胞受体和促炎信号的转录标志。只有 22 个月大的小鼠部分类似于活化的 T 细胞表型。在 43 名接受颈动脉内膜切除术的患者的验证队列中，由多色流式细胞术定义的斑块中活化免疫细胞亚群的丰度与临床动脉粥样硬化的程度相关。 结论 综合 scRNA-seq 揭示了小鼠和人颈动脉粥样硬化的免疫细胞组成存在显着差异——这一发现质疑了标准小鼠模型在适应性免疫细胞研究中的转化价值。临床关联表明 T 细胞驱动（自身）免疫在人类斑块形成和不稳定性中具有特定作用。