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

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.