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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
Author(s) -
Boni Carolina,
Lampertico Pietro,
Talamona Lavinia,
Giuberti Tiziana,
Invernizzi Federica,
Barili Valeria,
Fisicaro Paola,
Rossi Marzia,
Cavallo Maria Cristina,
Vecchi Andrea,
Pedrazzi Giuseppe,
Alfieri Arianna,
Colombo Massimo,
Missale Gabriele,
Ferrari Carlo
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28155
Subject(s) - hbsag , immunology , hepatitis b virus , nkg2d , natural killer cell , cytotoxic t cell , t cell , medicine , interleukin 21 , biology , virus , immune system , in vitro , biochemistry
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.(H epatology 2015;62:1697–1709)