Background and Aims: Chronic liver disease due to metabolic dysfunction–associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. Approach and Results: In these studies, we evaluated differences in T cell phenotype in the context of liver disease. Accordingly, we isolated liver resident T cell populations from humans with cirrhosis and from mice with diet-induced MASH. Using both 5’ single-cell sequencing and flow cytometry, we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. Conclusions: MASH-induced human cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1, TIGIT, and TOX. Overall, this study establishes for the first time that T cells undergo Ag-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.

中文翻译：

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Ag 驱动的 CD8+ T 细胞克隆扩增是人类和小鼠 MASH 的一个显着特征


背景和目的：代谢功能障碍相关脂肪性肝炎（MASH）引起的慢性肝病是一种迅速增长的全球流行病。 MASH 进展是炎症损伤和肝脏免疫反应失调之间复杂相互作用的结果。研究表明，MASH 期间 T 淋巴细胞会在肝脏中积聚，但 T 细胞在肝脏中积聚的原因和后果仍不清楚。我们的研究旨在确定来自人类肝硬化肝脏和 MASH 动物模型的 T 细胞的表型和 T 细胞受体多样性，以开始解析它们在疾病中的功能。方法和结果：在这些研究中，我们评估了肝病背景下 T 细胞表型的差异。因此，我们从患有肝硬化的人类和患有饮食诱导的 MASH 的小鼠中分离出肝脏驻留 T 细胞群。使用 5' 单细胞测序和流式细胞术，我们定义了健康和疾病期间肝脏驻留 T 细胞的表型和 T 细胞受体库。结论：MASH 诱导的人类肝硬化和饮食诱导的小鼠 MASH 导致肝脏中活化和克隆扩增的 T 细胞积聚。肝脏中克隆扩增的 T 细胞表达慢性抗原刺激的标记物，包括PD1 ,蒂吉特， 和毒性。总体而言，这项研究首次证实 T 细胞在 MASH 进展过程中经历 Ag 依赖性克隆扩增和功能分化。这些研究可能有助于识别在 MASH 过程中驱动 T 细胞激活、克隆扩增和招募至肝脏的抗原靶标。