IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia

作者：Mengting Liu, Weida Meng, Yuehua Chen, Shaojing Wu, Manning Qian, Di Chen, Jie Zhang, Jianxiang Dong, Yi Yang, Jingying Jiang, T F Li, Shi Qx, Xufang Gu, Shaoyang Sun, Wenqing Qiu, Rui Dong, Xi Zhang, Shan Zheng, G Q Chen, Yun Liu · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.08.736942 · 研究领域：Pediatric Hepatobiliary Diseases and Treatments、Liver Diseases and Immunity、Drug Transport and Resistance Mechanisms

Abstract Background Biliary atresia (BA) is a severe neonatal liver disease characterized by progressive fibrosis and bile duct obliteration. Objective Although immune dysregulation is implicated in the pathogenesis of BA, the specific mechanisms driving bile duct injury remain incompletely understood. This study aimed to characterize tertiary lymphoid structures (TLSs) within extrahepatic biliary remnants (EBRs), identify their cellular mediators, and evaluate the therapeutic potential of targeting IL-21 receptor signaling. Design We performed integrated bulk RNA sequencing, single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and flow cytometry on clinical samples from BA patients and non-BA cholestatic controls. TLS maturation was assessed by CD23 immunohistochemistry in EBRs from 148 BA patients and correlated with clinical parameters. Anti-IL-21R antibody treatment was evaluated in a rhesus rotavirus-induced BA mouse model, with treatment initiated on day 4 post-infection. Results TLSs were identified in BA EBRs with significantly higher prevalence than in matched liver tissues. Mature TLSs containing CD23⁺ germinal centers were associated with elevated serum matrix metalloproteinase-7, more advanced hepatic fibrosis, and localized autoantibody deposition on injured bile ducts. Single-cell profiling revealed expanded CD4 + T peripheral helper (Tph) cells expressing IL-21 and CXCL13 within TLS-containing EBRs. Tph cells were enriched in per...