Cargando…

Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in...

Descripción completa

Detalles Bibliográficos
Autores principales: Das, Abhishek, Hoare, Matthew, Davies, Nathan, Lopes, A. Ross, Dunn, Claire, Kennedy, Patrick T.F., Alexander, Graeme, Finney, Helene, Lawson, Alistair, Plunkett, Fiona J., Bertoletti, Antonio, Akbar, Arne N., Maini, Mala K.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526205/
https://www.ncbi.nlm.nih.gov/pubmed/18695005
http://dx.doi.org/10.1084/jem.20072076
_version_ 1782158732323454976
author Das, Abhishek
Hoare, Matthew
Davies, Nathan
Lopes, A. Ross
Dunn, Claire
Kennedy, Patrick T.F.
Alexander, Graeme
Finney, Helene
Lawson, Alistair
Plunkett, Fiona J.
Bertoletti, Antonio
Akbar, Arne N.
Maini, Mala K.
author_facet Das, Abhishek
Hoare, Matthew
Davies, Nathan
Lopes, A. Ross
Dunn, Claire
Kennedy, Patrick T.F.
Alexander, Graeme
Finney, Helene
Lawson, Alistair
Plunkett, Fiona J.
Bertoletti, Antonio
Akbar, Arne N.
Maini, Mala K.
author_sort Das, Abhishek
collection PubMed
description The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.
format Text
id pubmed-2526205
institution National Center for Biotechnology Information
language English
publishDate 2008
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-25262052009-03-01 Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection Das, Abhishek Hoare, Matthew Davies, Nathan Lopes, A. Ross Dunn, Claire Kennedy, Patrick T.F. Alexander, Graeme Finney, Helene Lawson, Alistair Plunkett, Fiona J. Bertoletti, Antonio Akbar, Arne N. Maini, Mala K. J Exp Med Articles The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment. The Rockefeller University Press 2008-09-01 /pmc/articles/PMC2526205/ /pubmed/18695005 http://dx.doi.org/10.1084/jem.20072076 Text en © 2008 Das et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Articles
Das, Abhishek
Hoare, Matthew
Davies, Nathan
Lopes, A. Ross
Dunn, Claire
Kennedy, Patrick T.F.
Alexander, Graeme
Finney, Helene
Lawson, Alistair
Plunkett, Fiona J.
Bertoletti, Antonio
Akbar, Arne N.
Maini, Mala K.
Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection
title Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection
title_full Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection
title_fullStr Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection
title_full_unstemmed Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection
title_short Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection
title_sort functional skewing of the global cd8 t cell population in chronic hepatitis b virus infection
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526205/
https://www.ncbi.nlm.nih.gov/pubmed/18695005
http://dx.doi.org/10.1084/jem.20072076
work_keys_str_mv AT dasabhishek functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT hoarematthew functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT daviesnathan functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT lopesaross functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT dunnclaire functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT kennedypatricktf functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT alexandergraeme functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT finneyhelene functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT lawsonalistair functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT plunkettfionaj functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT bertolettiantonio functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT akbararnen functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection
AT mainimalak functionalskewingoftheglobalcd8tcellpopulationinchronichepatitisbvirusinfection