Open AccessFrequency and role of NKp46 and NKG2A in hepatitis B virus infection
Author(s) -
Teppei Yoshioka,
Tomohide Tatsumi,
Takuya Miyagi,
Kaori Mukai,
Kazuaki Nishio,
Akira Nishio,
Yoshinobu Yokoyama,
Takahiro Suda,
Tadashi Kegasawa,
Minoru Shigekawa,
Hayato Hikita,
Ryotaro Sakamori,
Tetsuo Takehara
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0174103
Subject(s) - flow cytometry , titer , hepatitis b virus , immunology , receptor , ligand (biochemistry) , antibody , virology , hepatitis b , cytotoxicity , biology , microbiology and biotechnology , in vitro , virus , biochemistry
Background and Aim Natural 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/Method Peripheral 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-γ production in NK cells were evaluated using RT-PCR and flow cytometry. Results CHB patients were classified into treatment-naïve 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-γ 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-naïve 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 and IFN-γ expression was lower in the NKp46 high NKG2A high subset than in the other subsets. Conclusion The 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.