Mucosal-associated invariant T cells promote ductular reaction through amphiregulin in biliary atresia

作者：Man-Huan Xiao, Sihan Wu, Peishi Liang, Dong Ma, Jiang Zhang, Huadong Chen, Zhihai Zhong, Juncheng Liu, Hong Jiang, Xuyang Feng, Zhenhua Luo · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.105138 · 被引用次数：20 · 研究领域：Immune Cell Function and Interaction、Pediatric Hepatobiliary Diseases and Treatments、Autoimmune and Inflammatory Disorders Research

BACKGROUND: Biliary atresia (BA) is a neonatal fibro-inflammatory cholangiopathy with ductular reaction as a key pathogenic feature predicting poor survival. Mucosal-associated invariant T (MAIT) cells are enriched in human liver and display multiple roles in liver diseases. We aimed to investigate the function of MAIT cells in BA. METHODS: First, we analyzed correlations between liver MAIT cell and clinical parameters (survival, alanine transaminase, bilirubin, histological inflammation and fibrosis) in two public cohorts of patients with BA (US and China). Kaplan-Meier survival analysis and spearman correlation analysis were employed for survival data and other clinical parameters, respectively. Next, we obtained liver samples or peripheral blood from BA and control patients for bulk RNA sequencing, flow cytometry analysis, immunostaning and functional experiments of MAIT cells. Finally, we established two in vitro co-culture systems, one is the rhesus rotavirus (RRV) infected co-culture system to model immune dysfunction of human BA which was validated by single cell RNA sequencing and the other is a multicellular system composed of biliary organoids, LX-2 and MAIT cells to evaluate the role of MAIT cells on ductular reaction. FINDINGS: Liver MAIT cells in BA were positively associated with low survival and ductular reaction. Moreover, liver MAIT cells were activated, exhibited a wound healing signature and highly expressed growth factor Amphiregulin (AREG) in a T cell rec...