Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis

Hao-Xian Zhu, Shu-Han Yang, Cai-Yue Gao, Zhen-Hua Bian, Xiao-Min Chen, Rong-Rong Huang, Qian-Li Meng, Xin Li, Haosheng Jin, Koichi Tsuneyama, Ying Han, Liang Li (), Zhi-Bin Zhao (), M. Eric Gershwin () and Zhe-Xiong Lian ()
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Hao-Xian Zhu: South China University of Technology
Shu-Han Yang: South China University of Technology
Cai-Yue Gao: Southern Medical University
Zhen-Hua Bian: South China University of Technology
Xiao-Min Chen: South China University of Technology
Rong-Rong Huang: Southern Medical University
Qian-Li Meng: Southern Medical University
Xin Li: Southern Medical University
Haosheng Jin: Southern Medical University
Koichi Tsuneyama: Tokushima University Graduate School
Ying Han: Air Force Military Medical University
Liang Li: Southern Medical University
Zhi-Bin Zhao: Southern Medical University
M. Eric Gershwin: University of California Davis
Zhe-Xiong Lian: Southern Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- 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.

Date: 2024
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DOI: 10.1038/s41467-024-46654-5

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