LAG3 erythroid progenitor cells inhibit HBsAg seroclearance during finite pegylated interferon treatment through LAG3 and TGF-β.

HBsAg seroclearance, the ideal aim of anti-hepatitis B virus (HBV) treatment, cannot be achieved easily. Anemia is another common issue for chronic hepatitis B (CHB) patients, which leads to elevation of erythroid progenitor cells (EPCs) and immune suppression in cancer. This study investigated the role of EPCs in HBsAg seroclearance following pegylated interferon-α (PEG-IFN) treatment. CD45EPC accumulation in CHB patients and an AAV/HBV mice model was found in the circulation and liver by flow cytometry and immunofluorescence tests. Wright-Giemsa staining showed that these pathological CD45EPCs presented elevated erythroid cells with relative immature morphologies and atypical cells compared with the control cells. CD45EPCs were associated with immune tolerance and decreased HBsAg seroclearance during finite PEG-IFN treatment. CD45EPCs suppressed antigen non-specific T cell activation and HBV-specific CD8T cells, partially through transforming growth factor β (TGF-β). RNA-seq revealed that CD45EPCs in patients with CHB presented a distinct gene expression profile compared with CD45EPCs and CD45EPCs from cord blood. Notably, CD45EPCs from patients with CHB expressed high level of Lymphocyte-activation gene 3 (LAG3), an immune checkpoint molecule, and were then defined as LAG3EPCs. LAG3EPCs diminished the function of antigen presenting cells through LAG3, which was another mechanism by which LAG3EPCs' suppressed HBV-specific CD8T cells. Anti-LAG3 and anti-TGF-β combination treatment decreased serum HBeAg, HBV DNA levels and HBsAg level, as well as HBsAg-expression in hepatocytes during PEG-IFN treatment in the AAV/HBV mice model. Conclusions: LAG3EPCs inhibited the efficacy of PEG-IFN treatment on HBsAg seroclearance induced by LAG3 and TGF-β. Anti-LAG3, anti-TGF-β and PEG-IFN combination treatment might facilitate HBV clearance.