Madani Jood, Li Jiafeng, Ching Ma Enrica Angela, Vranjkovic Agatha, Jorritsma Katrina, Hasim Mohamed S, Daneshmand Manijeh, Campeau Natasha, Lawton David A, Bagheri Salman, Cheung Angela C, Mulvihill Erin E, Bruin Jennifer E, Ardolino Michele, Crawley Angela M
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Eur J Immunol. 2025 Aug;55(8):e70026. doi: 10.1002/eji.70026.
Immune dysfunction in liver disease contributes to significant morbidities, depending on liver damage severity and aetiology. We previously reported long-lasting generalized CD8 T cell hyperfunction in chronic HCV infection with advanced fibrosis, yet its separation from viral and fibrosis-driven effects, as well as clinical outcomes of advanced fibrosis, remains unclear. In a murine model of carbon tetrachloride-induced progressive liver fibrosis, advanced fibrosis was observed by 12 weeks, with pathologies similar to those of human chronic HCV infection. Blood-circulating CD8 T cells showed IFN-γ and granzyme B (GrB) hyperfunction in response to anti-CD3/28 stimulation, as well as impaired responses to ectopic tumour challenge and anti-PD-1/CTLA-4 immunotherapy. Hyperfunction and impaired tumour responses were retained despite liver insult cessation. In a 45% HFD model, which induced steatosis and minimal fibrosis, IFN-γ and GrB hyperfunction was also observed in blood-circulating CD8 T cells. This study highlights a prolonged systemic CD8 T cell dysfunction acquired during progressive liver disease, associated with impaired antitumour and immunotherapy responses. These mirror the bulk CD8 T cell dysfunction observed in advanced liver diseases in humans, suggesting that these models could be valuable for future mechanistic studies aimed at identifying targets to help improve clinical outcomes in chronic liver disease.
肝病中的免疫功能障碍会导致严重的发病率，这取决于肝损伤的严重程度和病因。我们之前报道过，在伴有晚期纤维化的慢性丙型肝炎病毒（HCV）感染中，存在持久的全身性CD8 T细胞功能亢进，但尚不清楚其与病毒和纤维化驱动效应的区别，以及晚期纤维化的临床结局。在四氯化碳诱导的进行性肝纤维化小鼠模型中，12周时观察到晚期纤维化，其病理与人类慢性HCV感染相似。血液循环中的CD8 T细胞在抗CD3/28刺激下表现出IFN-γ和颗粒酶B（GrB）功能亢进，对异位肿瘤攻击和抗PD-1/CTLA-4免疫治疗的反应受损。尽管停止了肝脏损伤，但功能亢进和肿瘤反应受损的情况仍然存在。在诱导脂肪变性和轻度纤维化的45%高脂饮食（HFD）模型中，血液循环中的CD8 T细胞也观察到IFN-γ和GrB功能亢进。这项研究强调了在进行性肝病期间获得的长期全身性CD8 T细胞功能障碍，这与抗肿瘤和免疫治疗反应受损有关。这些反映了在人类晚期肝病中观察到的大量CD8 T细胞功能障碍，表明这些模型对于未来旨在确定有助于改善慢性肝病临床结局的靶点的机制研究可能具有重要价值。
