Wang Han, Wang Shuhui, Lei Yu, Chen Yu, Huang Zheng, Nie Shangshu, Han Ping, Xia Yujia, Feng Xinxia, Yu Jianyu, Li Hao, Zhong Claire Chenwen, Yan Wei, Huang Hai, Tian Dean, Liu Mei
Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Hepatology. 2025 Jun 9. doi: 10.1097/HEP.0000000000001419.
Treatment of autoimmune hepatitis (AIH) remains challenging and primarily relies on corticosteroid therapy. Regulatory T cells (Tregs), essential for maintaining immune homeostasis and preventing various autoimmune diseases, present a potential therapeutic target for AIH. However, the role of Tregs in AIH pathogenesis remains unclear.
In a well-established AIH model induced by hydrodynamic transfection of cytochrome P450 2D6 (CYP2D6) plasmid into mouse liver, Tregs were found to increase in number as the disease progressed. Despite the increased hepatic Treg presence, the proportions of effector T cells also rose, contributing to disease progression. Systemic Treg depletion using FoxP3-DTR/eGFP mice exacerbated AIH progression, while adoptive Treg transfer failed to alleviate liver inflammation and fibrosis, highlighting intrahepatic Treg dysfunction. Single-cell RNA sequencing of hepatic Tregs using the 10× Genomics platform identified impaired suppressive function and a shift toward proinflammatory phenotypes, contrasting with enhanced suppressive capacity observed in peripheral Tregs. This intrahepatic Treg dysfunction was associated with elevated hepatic serum amyloid A1 (SAA1) levels, which impaired Tregs through toll-like receptor 2. Liver-specific AAV8-mediated shSAA1 therapy restored Treg function and ameliorated AIH symptoms, while the adoptive transfer of Tregs lacking toll-like receptor 2 significantly improved disease outcomes.
Intrahepatic Tregs exhibit a diminished suppressive phenotype and an enhanced effector phenotype, failing to control the escalating inflammation in AIH. AIH treatment should not only focus on increasing Treg numbers but also on restoring their functional capacity.
自身免疫性肝炎（AIH）的治疗仍然具有挑战性，主要依赖于皮质类固醇疗法。调节性T细胞（Tregs）对于维持免疫稳态和预防各种自身免疫性疾病至关重要，是AIH潜在的治疗靶点。然而，Tregs在AIH发病机制中的作用仍不清楚。
在通过将细胞色素P450 2D6（CYP2D6）质粒经 hydrodynamic转染至小鼠肝脏诱导建立的AIH模型中，发现随着疾病进展Tregs数量增加。尽管肝脏中Tregs数量增加，但效应T细胞的比例也上升，促进了疾病进展。使用FoxP3-DTR/eGFP小鼠进行全身Treg清除会加剧AIH进展，而Treg过继转移未能减轻肝脏炎症和纤维化，突出了肝内Treg功能障碍。使用10×基因组学平台对肝内Tregs进行单细胞RNA测序，发现其抑制功能受损并向促炎表型转变，这与外周Tregs中观察到的增强抑制能力形成对比。这种肝内Treg功能障碍与肝脏血清淀粉样蛋白A1（SAA1）水平升高有关，SAA1通过Toll样受体2损害Tregs。肝脏特异性AAV8介导的shSAA1治疗恢复了Treg功能并改善了AIH症状，而缺乏Toll样受体2的Tregs过继转移显著改善了疾病结局。
肝内Tregs表现出抑制表型减弱和效应表型增强，无法控制AIH中不断升级的炎症。AIH治疗不仅应关注增加Tregs数量，还应关注恢复其功能能力。
