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

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 () and Jianhua Li ()
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Xiaofang Li: Fudan University
Wenxuan Sun: Fudan University
Xiaolan Xu: Fudan University
Qirong Jiang: Fudan University
Yuheng Shi: Fudan University
Huixi Zhang: Fudan University
Weien Yu: Fudan University
Bisheng Shi: Fudan University
Simin Wan: Fudan University
Jiangxia Liu: Fudan University
Wuhui Song: Fudan University
Jiming Zhang: Fudan University
Zhenghong Yuan: Fudan University
Jianhua Li: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59985-8

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