Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults

Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8+ T cells are at an early or late stage of differentiation and whether telomere e...

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Main Authors:	Riddell, Natalie E, Griffiths, Stephen J, Rivino, Laura, King, David C B, Teo, Guo H, Henson, Sian M, Cantisan, Sara, Solana, Rafael, Kemeny, David M, MacAry, Paul A, Larbi, Anis, Akbar, Arne N
Format:	Online
Language:	English
Published:	BlackWell Publishing Ltd 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368162/

id	pubmed-4368162
recordtype	oai_dc
spelling	pubmed-43681622015-04-27 Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults Riddell, Natalie E Griffiths, Stephen J Rivino, Laura King, David C B Teo, Guo H Henson, Sian M Cantisan, Sara Solana, Rafael Kemeny, David M MacAry, Paul A Larbi, Anis Akbar, Arne N Original Articles Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8+ T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8+ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8+ CD45RA+ CD27− T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8+ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8+ T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8+ T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion. BlackWell Publishing Ltd 2015-04 2015-03-09 /pmc/articles/PMC4368162/ /pubmed/25314332 http://dx.doi.org/10.1111/imm.12409 Text en © 2014 The Authors. Immunology published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Riddell, Natalie E Griffiths, Stephen J Rivino, Laura King, David C B Teo, Guo H Henson, Sian M Cantisan, Sara Solana, Rafael Kemeny, David M MacAry, Paul A Larbi, Anis Akbar, Arne N
spellingShingle	Riddell, Natalie E Griffiths, Stephen J Rivino, Laura King, David C B Teo, Guo H Henson, Sian M Cantisan, Sara Solana, Rafael Kemeny, David M MacAry, Paul A Larbi, Anis Akbar, Arne N Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
author_facet	Riddell, Natalie E Griffiths, Stephen J Rivino, Laura King, David C B Teo, Guo H Henson, Sian M Cantisan, Sara Solana, Rafael Kemeny, David M MacAry, Paul A Larbi, Anis Akbar, Arne N
author_sort	Riddell, Natalie E
title	Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
title_short	Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
title_full	Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
title_fullStr	Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
title_full_unstemmed	Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
title_sort	multifunctional cytomegalovirus (cmv)-specific cd8+ t cells are not restricted by telomere-related senescence in young or old adults
description	Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8+ T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8+ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8+ CD45RA+ CD27− T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8+ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8+ T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8+ T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.
publisher	BlackWell Publishing Ltd
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368162/
_version_	1613201658035044352

Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults

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