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Key role of T cell defects in age-related vulnerability to West Nile virus
West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50× more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demo...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806630/ https://www.ncbi.nlm.nih.gov/pubmed/19901080 http://dx.doi.org/10.1084/jem.20090222 |
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author | Brien, James D. Uhrlaub, Jennifer L. Hirsch, Alec Wiley, Clayton A. Nikolich-Žugich, Janko |
author_facet | Brien, James D. Uhrlaub, Jennifer L. Hirsch, Alec Wiley, Clayton A. Nikolich-Žugich, Janko |
author_sort | Brien, James D. |
collection | PubMed |
description | West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50× more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12× fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly. |
format | Text |
id | pubmed-2806630 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28066302010-05-23 Key role of T cell defects in age-related vulnerability to West Nile virus Brien, James D. Uhrlaub, Jennifer L. Hirsch, Alec Wiley, Clayton A. Nikolich-Žugich, Janko J Exp Med Article West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50× more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12× fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly. The Rockefeller University Press 2009-11-23 /pmc/articles/PMC2806630/ /pubmed/19901080 http://dx.doi.org/10.1084/jem.20090222 Text en © 2009 Brien 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 | Article Brien, James D. Uhrlaub, Jennifer L. Hirsch, Alec Wiley, Clayton A. Nikolich-Žugich, Janko Key role of T cell defects in age-related vulnerability to West Nile virus |
title | Key role of T cell defects in age-related vulnerability to West Nile virus |
title_full | Key role of T cell defects in age-related vulnerability to West Nile virus |
title_fullStr | Key role of T cell defects in age-related vulnerability to West Nile virus |
title_full_unstemmed | Key role of T cell defects in age-related vulnerability to West Nile virus |
title_short | Key role of T cell defects in age-related vulnerability to West Nile virus |
title_sort | key role of t cell defects in age-related vulnerability to west nile virus |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806630/ https://www.ncbi.nlm.nih.gov/pubmed/19901080 http://dx.doi.org/10.1084/jem.20090222 |
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