Hepatitis B surface antigen directly alters Dendritic cell-mediated Natural Killer cell responses

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

Blood-derived DC subsets were pre-exposed to HBsAg and then co-cultured with NK cells under various stimulation conditions. We subsequently evaluated the modulations of DC, and the phenotypic and functional responses of NK cells. Similarly, DC subsets were exposed to serum from HBV-infected individuals with varying levels of HBsAg or directly purified from HBV patients to assess their ability to stimulate NK cell responses.

Our findings show that HBsAg disrupts cDC2-mediated NK cell activation through Toll-like receptor (TLR)7/8-dependent pathways and cDC1-mediated NK cell degranulation via TLR3-dependent mechanisms. Exposure of pDC to HBsAg alters NK cell activation, phenotype and degranulation through TLR9-dependent pathways. This impairment was recapitulated following exposure to serum from HBV-infected patients in an HBsAg-dependent manner. Consistently, circulating HBsAg in patients with chronic HBV infection was associated with impaired pDC-mediated NK cell cytotoxicity.

These results uncover key mechanisms by which HBsAg modulates pDC-NK cell interactions, shedding light on how HBV evades innate immune responses and contributes to immune dysfunction.