Suppressed natural killer (NK) cell functionality potentially contributes to hepatitis B virus (HBV) persistence during chronic hepatitis B, although the underlying mechanism is not entirely clear. A peculiar feature of HBV is the secretion of large amounts of hepatitis B surface antigen (HBsAg) by hepatocytes. However, the effects of varying HBsAg quantities on the phenotype and function of systemic NK cells remains to be determined.

In the present study, we selected 80 patients expressing varying amounts of HBsAg and categorized them into four groups according to HBsAg quantity. We measured and compared the NK cell phenotypes and functions among these groups and in healthy controls. Overall, we found the following: (i) the NK cell pool was reshaped during CHB infections with increasing CD56^bright NK cells observed in patients with high HBsAg levels; (ii) NK cells were less mature in CHB patients as assessed by the presence of Eomes^-T-bet⁺; (iii) NK cells in patients with low HBsAg levels (<100 IU/ml) displayed the activated phenotype with the increased proliferation of Ki-67 and the activation markers CD38 and Granzyme B whilst exhibiting defective functional responses; (iv) CD56^bright NK cell activation markers were negatively correlated with surface antigen levels; and (v) HBsAg suppressed the NK cell functional responses but not the NK cell phenotype in vitro.

In conclusion, this comprehensive study investigating potential relationship between different surface antigen levels and NK cell functions and phenotype suggests that NK cells may indeed play a role in controlling the systemic HBV infection.