Abstract
Natural killer (NK) cells play an important role in hepatitis B virus (HBV) infection control, and are regulated by a complex network of activating and inhibitory receptors. However, NK cell activity in HBV patients remains poorly understood. The objective of this study was to investigate the phenotypic and functional characteristics of circulating NK cells in patients during different chronic hepatitis B (CHB) infection stages. We investigated NK cell phenotypes, receptor expression and function in 86 CHB patients and 20 healthy controls. NK cells were purified and NK cell subsets were characterized by flow cytometry. Cytotoxic activity (CD107a) and interferon-gamma (IFN-γ) secretion were examined, and Natural Killer p46 (NKP46) blockade and spontaneous NK cell cytolytic activity against K562, HepG2 and HepG2.215 cell lines was studied. Activating NKp46 receptor expression was higher in inactive HBsAg carriers when compared with other groups (p = 0.008). NKp46 expression negatively correlated with HBV DNA (R = -0.253, p = 0.049) and ALT (R = -0.256, p = 0.045) levels. CD107a was higher in immune-activated groups when compared with immune-tolerant groups (p = 0.039). CD107a expression was related to viral load (p = 0.02) and HBeAg status (p = 0.024). In vitro NKp46 blockade reduced NK cell cytolytic activity against HepG2 and HepG2.215 cell lines (p = 0.02; p = 0.039). Furthermore, NK cells from high viral load CHB patients displayed significantly lower specific cytolytic activity against anti-NKp46-loaded K562 targets (p = 0.0321). No significant differences were observed in IFN-γ secretion (p > 0.05). In conclusion, NKp46 expression regulates NK cell cytolytic function. NKp46 may moderate NK cell activity during HBV replication suppression and HBV-associated liver damage and may be critical for NK cell activity during CHB infection.
Highlights
Hepatitis B virus (HBV) infection is a major global health concern that affects approximately 240 million people worldwide [1,2]
NKp46 expression negatively correlated with HBV DNA and alanine aminotransferase (ALT)
Analysis of the correlations between Natural killer (NK) cell receptor expression and the clinical parameters of chronic HBV (CHB) patients indicated that NKp46 expression negatively correlated with HBV DNA (R = -0.253, p = 0.049) and ALT (R = -0.256, p = 0.045) levels
Summary
Hepatitis B virus (HBV) infection is a major global health concern that affects approximately 240 million people worldwide [1,2]. HBV infections follow a course that is divided into four. NKp46 Controls HBV Replication and Liver Inflammation phases: immune tolerance, immune clearance, low replication and reactivation [3]. Because HBV is not cytopathogenic, the host immune responses induced by viral persistence are generally thought to be responsible for disease progression in chronic HBV (CHB) patients [4]. Because acute and CHB infections involve different immune responses, a complete understanding of the diversity of CHB infections and host immune responses remains elusive [5]. It is generally accepted that HBV-specific T cells play an important role in CHB infection induced hepatocellular damage [6,7]; recent studies report that other innate immune effector mechanisms may be responsible for viral clearance and liver pathogenesis [3]
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