title: 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.
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.
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: M
authors.initials: M
authors.lastname: Nandi
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Pal
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: D
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: B C
authors.initials: BC
authors.lastname: Chakraborty
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: M
authors.initials: M
authors.lastname: Khatun
authors.affiliation: CU-BD Centre of Excellence for Nanobiotechnology, Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, India.
authors.forename: D
authors.initials: D
authors.lastname: Bhowmick
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: R K
authors.initials: RK
authors.lastname: Mondal
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.affiliation: Division of Gastrointestinal and Liver Pathology, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: R
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: A
authors.initials: A
authors.lastname: Santra
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: M
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: A
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India. Electronic address: seemdatt@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Datta
mesh_terms: D015415:Biomarkers; D015550:Cell Degranulation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000175:diagnosis / Q000276:immunology* / Q000821:virology*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008111:Liver Function Tests; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D006513:Hepatitis B e Antigens; D054353:Perforin; D053804:Granzymes
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