Hepatitis B Surface Antigen Directly Alters Dendritic Cell-Mediated Natural Killer Cell Responses

Hepatitis B, caused by the hepatitis B virus, is a significant global health concern, often leading to chronic hepatitis B in individuals unable to mount an effective immune response. Chronic hepatitis B virus substantially increases the risk of severe liver diseases, including cirrhosis and hepatocellular carcinoma. Dendritic cells and natural killer cells play crucial roles in the early immune response to hepatitis B virus, but their function is compromised in patients with chronic hepatitis B. We investigated how hepatitis B surface antigen influences the interplay between dendritic cell subpopulations and natural killer cells.

Blood-derived dendritic cell subsets were pre-exposed to hepatitis B surface antigen and then cocultured with natural killer cells under various stimulation conditions. We subsequently evaluated the modulations of dendritic cells and the phenotypic and functional responses of natural killer cells. Similarly, dendritic cell subsets were exposed to serum from hepatitis B virus-infected individuals with varying levels of hepatitis B surface antigen or directly purified from patients with hepatitis B virus to assess their ability to stimulate natural killer cell responses.

Our findings show that hepatitis B surface antigen disrupts type 2 conventional dendritic cell-mediated natural killer cell activation through Toll-like receptor 7 and 8-dependent pathways and type 1 dendritic cell-mediated natural killer cell degranulation via Toll-like receptor 3-dependent mechanisms. Exposure of plasmacytoid dendritic cells to hepatitis B surface antigen alters natural killer cell activation, phenotype, and degranulation through Toll-like receptor 9-dependent pathways. This impairment was recapitulated following exposure to serum from hepatitis B virus-infected patients in a hepatitis B surface antigen-dependent manner. Consistently, circulating hepatitis B surface antigen in patients with chronic hepatitis B virus infection was associated with impaired plasmacytoid dendritic cell-mediated natural killer cell cytotoxicity.

These results uncover key mechanisms by which hepatitis B surface antigen modulates plasmacytoid dendritic cell-natural killer cell interactions, shedding light on how hepatitis B virus evades innate immune responses and contributes to immune dysfunction.