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

Clin Microbiol Infect. 2016 Aug;22(8):733.e9-733.e19. doi: 10.1016/j.cmi.2016.05.009. Epub 2016 May 18.

Abstract

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-γ 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-γ secretion and perforin-mediated CD4(+) T-cell lysis.

Keywords: CD4(+) T-cell depletion; Hepatitis B e-antigen-negative chronic Hepatitis B virus infection; Natural killer cells; Natural killer receptor ligands; Perforin; Reduced interferon-γ; TRAIL.

MeSH terms

  • Biomarkers
  • Cell Degranulation / immunology
  • Cytokines / biosynthesis
  • Disease Progression
  • Female
  • Granzymes / genetics
  • Granzymes / metabolism
  • Hepatitis B e Antigens / immunology*
  • Hepatitis B virus / immunology*
  • Hepatitis B, Chronic / diagnosis
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / virology*
  • Humans
  • Immunophenotyping
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Liver Function Tests
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Male
  • Perforin / genetics
  • Perforin / metabolism
  • Severity of Illness Index
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Hepatitis B e Antigens
  • Perforin
  • Granzymes