title: Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B.
abstract: Natural killer (NK) and hepatitis B virus (HBV)-specific T cells are functionally impaired in chronic hepatitis B (CHB). Understanding to what extent nucleos(t)ide analogue (NUC) therapy can improve T- and NK-cell responses is important in the perspective of immunomonitoring strategies for a safe and earlier NUC withdrawal and of novel combination therapies based on modulation of antiviral immunity. To gain further insights into T/NK-cell interplay, we studied NK-cell phenotype and function in hepatitis B e antigen-negative chronic HBV patients either untreated (25) or NUC treated (36 hepatitis B surface antigen [HBsAg](+) and 10 HBsAg(-)/hepatitis B surface antibody [anti-HBs](+)). Interferon-gamma, interleukin-2, and tumor necrosis factor alpha (TNF-α) production by HBV-specific T cells was also analyzed in NUC-treated patients. NK cells from chronic naïve patients showed an "inflammatory" phenotype defined by increased expression of TNF-related apoptosis-inducing ligand (TRAIL), CD38, and Ki67 that significantly declined upon viremia suppression and alanine aminotransferase normalization induced by NUC therapy. Reversion to a quiescent NK-cell phenotype was associated with restoration of the HBV-specific T-cell function. T- and NK-cell responses showed an inverse correlation, with an opposite behavior in individual NUC-treated patients. NK-cell depletion as well as TRAIL and NKG2D pathway blockade induced a significant improvement of the HBV-specific T-cell function.
  
  
  CONCLUSIONS
  NK cells can express regulatory activity on T cells in NUC-treated patients with prevalent inhibition of CD4 T cells, likely needed to limit persistent T-cell activation. NK-cell phenotype is modulated by NUC therapy and its reversion to quiescence mirrors efficient HBV-specific T-cell responses. Thus, changes of NK-cell phenotype may predict acquisition of antiviral control before anti-HBs seroconversion and represent the groundwork for future studies aimed at assessing whether NK phenotyping can be translated into the clinical practice to guide NUC suspension.
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Boni
authors.affiliation: Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Lampertico
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Talamona
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Giuberti
authors.affiliation: Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Barili
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fisicaro
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Cavallo
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchi
authors.affiliation: Department of Neuroscience, Biophysics and Medical Physics Unit, University of Parma, Parma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pedrazzi
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Alfieri
authors.affiliation: Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Missale
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrari
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D008297:Male; D009705:Nucleosides; D009711:Nucleotides; D010641:Phenotype; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D009705:Nucleosides; D009711:Nucleotides