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

Carolina Boni, Pietro Lampertico, Lavinia Talamona, Tiziana Giuberti, Federica Invernizzi, Valeria Barili, Paola Fisicaro, Marzia Rossi, Maria Cristina Cavallo, Andrea Vecchi, Giuseppe Pedrazzi, Arianna Alfieri, Massimo Colombo, Gabriele Missale, Carlo Ferrari

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1697-1709
Number of pages13
JournalHepatology
Volume62
Issue number6
DOIs
Publication statusPublished - Dec 1 2015

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Hepatitis Antigens
Natural Killer T-Cells
Hepatitis B e Antigens
Chronic Hepatitis B
Natural Killer Cells
Hepatitis B virus
T-Lymphocytes
Phenotype
Hepatitis B Surface Antigens
Antiviral Agents
Tumor Necrosis Factor-alpha
TNF-Related Apoptosis-Inducing Ligand
Hepatitis B Antibodies
Viremia
Therapeutics
Alanine Transaminase
Interferon-gamma
Interleukin-2
Immunity
Suspensions

ASJC Scopus subject areas

  • Hepatology

Cite this

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. / 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.

In: Hepatology, Vol. 62, No. 6, 01.12.2015, p. 1697-1709.

Research output: Contribution to journalArticle

Boni, C, Lampertico, P, Talamona, L, Giuberti, T, Invernizzi, F, Barili, V, Fisicaro, P, Rossi, M, Cavallo, MC, Vecchi, A, Pedrazzi, G, Alfieri, A, Colombo, M, Missale, G & Ferrari, C 2015, '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', Hepatology, vol. 62, no. 6, pp. 1697-1709. https://doi.org/10.1002/hep.28155
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. / 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. In: Hepatology. 2015 ; Vol. 62, No. 6. pp. 1697-1709.
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AU - Lampertico, Pietro

AU - Talamona, Lavinia

AU - Giuberti, Tiziana

AU - Invernizzi, Federica

AU - Barili, Valeria

AU - Fisicaro, Paola

AU - Rossi, Marzia

AU - Cavallo, Maria Cristina

AU - Vecchi, Andrea

AU - Pedrazzi, Giuseppe

AU - Alfieri, Arianna

AU - Colombo, Massimo

AU - Missale, Gabriele

AU - Ferrari, Carlo

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N2 - 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.

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