Hepatitis B virus surface antigen drives T cell immunity through non-canonical antigen presentation in mice

作者：Xiaofang Li, Wenxuan Sun, Xiaolan Xu, Qirong Jiang, Yuheng Shi, Huixi Zhang, Weien Yu, Bisheng Shi, Simin Wan, Jiangxia Liu, Wuhui Song, Jiming Zhang, Zhenghong Yuan, Jianhua Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59985-8 · 被引用次数：10 · 研究领域：Hepatitis B Virus Studies、Immunotherapy and Immune Responses、Hepatitis C virus research

Hepatitis B virus (HBV) exclusively infects hepatocytes and produces large amounts of subviral particles containing its surface antigen (HBsAg). T cell immunity is crucial for controlling and clearing HBV infection. However, the intercellular processes underlying HBsAg presentation to T cells are incompletely understood. Here, using preclinical mouse models, we show that, following HBsAg expression, the intrahepatic Batf3+XCR1+CCR7- conventional dendritic cell subset cDC1 presents HBsAg by MHC-I cross-dressing, driving CD8+ T cell response. Meanwhile, upon HBsAg access to lymphoid tissues, B cells acquire HBsAg directly in the follicles of lymphoid tissues and initiate CD4+ T cell responses sequentially in the follicular and interfollicular regions, guided by chemoattractant receptors CCR5 and EBI2, respectively. Finally, we identify ALCAM, LFA-1, and CD80 as key co-stimulatory signals essential for optimal T cell responses. Thus, these findings reveal the roadmap of non-canonical antigen presentation that drives T cell immunity against HBsAg, advancing novel therapeutic strategies for chronic HBV infection. The mechanism of HBsAg antigen presentation to T cells during liver HBV infection is incompletely understood. Here, the authors show that in mice, intrahepatic type I dendritic cells acquire HBsAg by MHC-I complexes through cross-dressing for CD8+ T cell priming, whereas CD4+ T cell responses rely on MHC-II-dependent antigen presentation by B cells in secondary lymphoid t...