Chronic HBV Infection Disrupts CCL5-Secreting cNK Cells and Attenuates Liver Accumulation and Activation of DCs and HBV-Specific T Cells.

Understanding the immunological mechanisms underlying chronic hepatitis B virus (HBV) infection-induced immune tolerance is critical for developing effective therapeutic strategies, yet the mechanisms by which natural killer (NK)-cell subsets regulate dendritic cell (DC)-mediated antiviral immunity during chronic HBV infection remain unclear. Here, we demonstrated that chronic HBV infection disrupted intrahepatic DCs accumulation and activation by suppressing CC chemokine ligand 5 (CCL5) production from hepatic NK cells. Importantly, chronic HBV infection reduced the number of hepatic conventional NK (cNK) cells, the main source of hepatic CCL5, whereas liver-resident NK (LrNK) cells increased and exhibited lower CCL5 expression and immunosuppressive features. Adoptive transfer of CCL5-competent hepatic cNK cells promoted DCs accumulation and activation, enhanced HBV-specific CD8+ T-cell responses, and facilitated viral clearance. Mechanistically, chronic HBV infection promoted the activation of adenosine A2a receptor (ADORA2A)/nuclear factor kappa-B (NF-κB) pathway in hepatic NK cells, thereby antagonizing NF-κB activation, reducing the proportion of cNK cells, suppressing CCL5 production, and ultimately impairing hepatic aggregation and activation of DCs, leading to defective anti-HBV immune responses. This study revealed a novel mechanism involved in chronic HBV infection-induced immune tolerance and indicated that targeting the ADORA2A/NFκB/CCL5 axis in cNK cells may represent a potential therapeutic strategy for chronic HBV infection.