Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.

Autor: Montali I; Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Ceccatelli Berti C; Department of Medicine and Surgery, University of Parma, Parma, Italy., Morselli M; Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy., Acerbi G; Department of Medicine and Surgery, University of Parma, Parma, Italy., Barili V; Department of Medicine and Surgery, University of Parma, Parma, Italy., Pedrazzi G; Department of Neuroscience - Biophysics and Medical Physics Unit, University of Parma, Parma, Italy., Montanini B; Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy., Boni C; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Alfieri A; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Pesci M; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Loglio A; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy., Degasperi E; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy., Borghi M; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy., Perbellini R; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy., Penna A; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Laccabue D; Department of Medicine and Surgery, University of Parma, Parma, Italy., Rossi M; Department of Medicine and Surgery, University of Parma, Parma, Italy., Vecchi A; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Tiezzi C; Department of Medicine and Surgery, University of Parma, Parma, Italy., Reverberi V; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Boarini C; Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy., Abbati G; Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy., Massari M; Unit of Infectious Diseases, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy., Lampertico P; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; CRC 'A. M. and A. Migliavacca' Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Missale G; Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Ferrari C; Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. Electronic address: carlo.ferrari@unipr.it., Fisicaro P; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. Electronic address: pfisicaro@ao.pr.it.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2023 Jul; Vol. 79 (1), pp. 50-60. Date of Electronic Publication: 2023 Mar 07.
DOI: 10.1016/j.jhep.2023.02.035
Abstrakt: Background & Aims: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies.
Methods: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed.
Results: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function.
Conclusions: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection.
Impact and Implications: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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