Frequency And Role Of Nkp46 And Nkg2a In Hepatitis B Virus Infection

Background and AimNatural Killer (NK) cells are involved in the control of viral infection. However, the role of NK cells in chronic hepatitis B (CHB) remains unclear. This study investigated the frequencies and roles of NK cells in CHB, with a focus on activating receptor NKp46 and inhibitory receptor NKG2A.Patients/MethodPeripheral blood lymphocytes were obtained from 71 CHB patients and 37 healthy subjects (HS). The expressions of NKp46 and NKG2A were analyzed using flow cytometry. The role of NKp46-ligand was assessed using an in vitro co-culture system. Cytotoxicity and IFN-gamma production in NK cells were evaluated using RT-PCR and flow cytometry.ResultsCHB patients were classified into treatment-naive patients with low HBV DNA titer (CHB-L; n = 28), high HBV DNA titer (CHB-H; n = 24) by the cut-off level of serum HBV DNA 4 log copies/ml, and patients receiving nucleos(t) ide analogue (CHB-NA; n = 19). The expressions of NKp46 and NKG2A were higher in CHB-H than in HS/CHB-L/CHB-NA. HepG2.2.15 had higher NKp46-ligand expression than HepG2. When NK cells from HS were co-cultured with HepG2.2.15, inhibition of the NKp46 and NKp46-ligand interaction by anti-NKp46 antibody significantly reduced cytolysis of HepG2.2.15 and IFN-gamma production. However, those reductions were not observed in co-culture with HepG2. Additionally, NK cells that highly expressed NKp46 also highly expressed NKG2A (NKp46 (high)NKG2A(high) subset). The frequencies of NKp46(high)NKG2A(high) subset in CHB-H were higher than those in HS/CHB-L/CHB-NA. Among treatment-naive CHB patients, the frequencies of NKp46(high)NKG2A(high) subset were positively correlated with serum ALT (P<0.01, r = 0.45) and HBV DNA (P<0.01, r = 0.59) levels. The expressions of Fas-L, STAT1, TRAIL and CD107a were higher IFN-gamma expression was lower in the NKp46(high)NKG2A(high) subset than in the other subsets.ConclusionThe NKp46 and NKp46-ligand interaction contributes to NK cell activation. A novel NK cell subset, the NKp46(high)NKG2A(high) subset, may be associated with liver injury and HBV replication.