Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigen-negative chronic hepatitis B virus infection

作者：Ghosh S; Nandi M; Pal S; Mukhopadhyay D; Chakraborty B C; Khatun M; Bhowmick D; Mondal R K; Das S; Das K; Ghosh R; Banerjee S; Santra A; Chatterjee M; Chowdhury A; Datta S^*

来源：Clinical Microbiology and Infection, 2016, 22(8): 733.e9.

DOI：10.1016/j.cmi.2016.05.009

• CD4(+) T-cell depletion
• Hepatitis B e-antigen-negative chronic
• Hepatitis B virus infection
• Natural killer cells
• Natural killer receptor ligands
• Perforin
• Reduced interferon-gamma
• TRAIL

Hepatitis B e-antigen negative (e(-)) chronic HBV infection (CHI) encompasses a heterogeneous clinical spectrum ranging from inactive carrier (IC) state to e(-) chronic hepatitis B (CHB), cirrhosis and hepatic decompensation. In the backdrop of dysfunctional virus-specific T cells, natural killer (NK) cells are emerging as innate effectors in CHI. We characterized CD3(-) CD56(+) NK cells in clinically well-defined, treatment-naive e(-) patients in IC, e(-) CHB or decompensated liver cirrhosis (LC) phase to appraise their role in disease progression. The NK cell frequencies increased progressively with disease severity (IC 8.2%, e(-)CHB 13.2% and LC 14.4%). Higher proportion of NK cells from LC/e(-)CHB expressed CD69, NKp46, NKp44, TRAIL and perforin, the last two being prominent features of CD56(bright) and CD56(dim) NK subsets, respectively. The frequencies of CD3(-) CD56(+) NK cells together with TRAIL(+) CD56(bright) and Perforin(+) CD56(dim) NK cells correlated positively with serum alanine transaminase levels in e(-)CHB/LC. K562 cell-stimulated NK cells from e(-) CHB/LC exhibited significantly greater degranulation but diminished interferon-g production than IC. Further, Perforin_ NK cell frequency inversely correlated with autologous CD4(+) T-cell count in e(-) patients and ligands of NK receptors were over-expressed in CD4(+) T cells from e(-) CHB/LC relative to IC. Co-culture of sorted CD56(dim) NK cells and CD4(+) T cells from e(-) CHB showed enhanced CD4(+) T-cell apoptosis, which was reduced by perforin inhibitor, concanamycin A, suggesting a possible perforin-dependent NK cell-mediated CD4(+) T-cell depletion. Moreover, greater incidence of perforin-expressing NK cells and decline in CD4(+) T cells were noticed intrahepatically in e(-) CHB than IC. Collectively, NK cells contribute to the progression of e(-) CHI by enhanced TRAIL- and perforin-dependent cytolytic activity and by restraining anti-viral immunity through reduced interferon-gamma secretion and perforin-mediated CD4(+) T-cell lysis. S.

• 出版日期2016-8