Chronic Disease Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), School of Medicine, South China University of Technology, Guangzhou, China.
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Nat Commun. 2024 Apr 5;15(1):2936. doi: 10.1038/s41467-024-46654-5.
Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12bIl2ra mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8 tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8 Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8 Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8 Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8 Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.
原发性胆汁性胆管炎（PBC）是一种胆汁淤积性自身免疫性肝病，其特征是针对肝内小胆管的自身反应性 T 细胞应答。在这里，我们使用 Il12bIl2ra 小鼠（DKO 小鼠）作为自身免疫性胆管炎模型，并证明 Cd8a 敲除或使用抗 CD8α 抗体可预防/减轻胆管免疫病理学。通过单细胞 RNA 测序分析，我们在 DKO 小鼠的肝脏中鉴定出 CD8 组织驻留记忆 T（Trm）细胞，这些细胞高度表达激活和细胞毒性相关标志物，并诱导胆管上皮细胞凋亡。肝 CD8 Trm 细胞还上调了几种免疫检查点分子的表达，包括 PD-1。我们描述了一种嵌合抗原受体，用于靶向表达 PD-1 的 CD8 Trm 细胞。用 PD-1 靶向 CAR-T 细胞治疗 DKO 小鼠可选择性耗尽肝 CD8 Trm 细胞并缓解自身免疫性胆管炎。我们的工作强调了 CD8 Trm 细胞的致病作用和 PD-1 靶向 CAR-T 细胞的潜在治疗用途。
