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

ABSTRACT 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.