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

• Published in: Nature communications Vol. 16; no. 1; pp. 4591 - 20
• Main Authors: Li, Xiaofang, Sun, Wenxuan, Xu, Xiaolan, Jiang, Qirong, Shi, Yuheng, Zhang, Huixi, Yu, Weien, Shi, Bisheng, Wan, Simin, Liu, Jiangxia, Song, Wuhui, Zhang, Jiming, Yuan, Zhenghong, Li, Jianhua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.05.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/31; 13/51; 14/28; 14/34; 14/35; 14/63; 38/77; 45/91; 59; 631/250/1619/554; 631/250/21/1293; 631/250/2152/1566/20; 64; 64/110; 64/60; 692/4020/4021/1607/234/2513/1549; 692/699/255/234/2513/1549; Animal models; Animals; Antigen presentation; Antigen Presentation - immunology; Antigens; B-Lymphocytes - immunology; CC chemokine receptors; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD80 antigen; Chronic infection; Cross-dressers; Dendritic cells; Dendritic Cells - immunology; Female; Follicles; Hepatitis; Hepatitis B; Hepatitis B - immunology; Hepatitis B surface antigen; Hepatitis B Surface Antigens - immunology; Hepatitis B Surface Antigens - metabolism; Hepatitis B virus - immunology; Hepatocytes; Humanities and Social Sciences; Humans; Immunity; Infections; LFA-1 antigen; Liver - immunology; Liver - virology; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoid tissue; Major histocompatibility complex; Mice; Mice, Inbred C57BL; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-59985-8

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 tissues.