Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals

Khan, Naeem; Shariff, Naseer; Cobbold, Mark; Bruton, Rachel; Ainsworth, Jenni A; Sinclair, Alan J; Nayak, Laxman; Moss, Paul A H

doi:10.4049/jimmunol.169.4.1984

Cited by 754Cytomegalovirus and herpesvirus researchT-cell and B-cell ImmunologyImmune Cell Function and Interaction

Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals

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Khan, Naeem, Shariff, Naseer, Cobbold, Mark, Bruton, Rachel, Ainsworth, Jenni A, Sinclair, Alan J, Nayak, Laxman, Moss, Paul A H·2002·The Journal of Immunology

DOI 10.4049/jimmunol.169.4.1984

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Abstract

The deterioration in immune function with aging is thought to make a major contribution to the increased morbidity and mortality from infectious disease in old age. One aspect of immune senescence is the reduction in CD8 T cell repertoire as due to the accumulation of oligoclonal, memory T cells and a reduction in the naive T cell pool. CD8 T cell clonal expansions accumulate with age, but their antigenic specificity remains unknown. In this study, we show that in elderly individuals seropositivity for human CMV leads to the development of oligoclonal populations of CMV-specific CTL that can constitute up to one-quarter of the total CD8 T cell population. Furthermore, CMV-specific CTL have a highly polarized membrane phenotype that is typical of effector memory cells (CD28−, CD57+, CCR7−). TCR analyses show that CMV-specific CTL have highly restricted clonality with greater restriction in the larger expansions. Clonal analysis of the total CD8 T cell repertoire was compared between CMV-seropositive and CMV-seronegative donors. Thirty-three percent more clonal expansions were observed in CMV-seropositive donors in comparison with seronegative individuals. These data implicate CMV as a major factor in driving oligoclonal expansions in old age. Such a dramatic accumulation of virus-specific effector CTL might impair the ability to respond to heterologous infection and may underlie the negative influence of CMV seropositivity on survival in the very elderly.

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Frequencies of CMV-specific and, to a lesser extent, EBV-specific CD8+ T cells tend to increase with age, protecting older individuals from CMV- and EBV-associated morbidities.
“frequencies of CMV-specific and to a lesser extent EBV-specific CD8+ T cells tend to increase, successfully protecting aging individuals from CMV- and EBV-associated morbidities”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Khan et al., 2002
T cells within both CD4+ and CD8+ compartments that have senescent characteristics increase during ageing.
“An important observation is that T cells within both CD4 + and CD8 + compartments that have senescent characteristics increase during ageing [25, 33-38] and are therefore likely to have an impact on altered immune function in older individuals.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [36]
The increase in senescent T cells during ageing is likely to have an impact on altered immune function in older individuals.
“An important observation is that T cells within both CD4 + and CD8 + compartments that have senescent characteristics increase during ageing [25, 33-38] and are therefore likely to have an impact on altered immune function in older individuals.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [36]
In the latent state, the intermittent production of viral antigens prevents contraction of virus-specific T cells.
“In the latent state, the intermittent production of viral antigens prevents contraction of virus-specific T cells.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [51]
This determines the phenomenon of memory cell inflation, leading to the emergence of vast populations of resting effector CD8+ and, to a lesser extent, CD4+ cells.
“As previously stated, this determines the phenomenon of memory cell inflation, leading to the emergence of vast populations of resting effector CD8+ and, to a lesser extent, CD4+ cells.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [51]

In older people, one or a few clonal populations can occupy more than 25% of the entire CD8+ cell pool.
“In older people, one or a few clonal populations can occupy more than 25% of the entire CD8+ cell pool (46, 51).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [51]
The virus is responsible for the generation of a large population of HCMV-specific CD8+ T cells, with a significant increase in highly differentiated CD8+ effector memory T cells, which expand clonally showing an effector memory phenotype characterized by low CD28 expression.
“Therefore, the virus is responsible for the generation of a large population of HCMV-specific CD8+ T cells, with a significant increase in highly differentiated CD8+ effector memory T cells, which expand clonally showing an effector memory phenotype characterized by low CD28 expression.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [51]
Large inter-individual differences exist, and it has been reported that 23% of the CD8+ T cell pool can become specific for just a single CMV epitope.
“Large inter-individual differences exist, and it has been reported that 23 % of the CD8+ T cell pool can become specific for just a single CMV epitope (Khan et al. 2002).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Khan et al. 2002
Programmed cell death is a balance between pro- and anti-apoptotic signals.
“These results, when interpreted with other data showing that CMV-specific cells exhibit high levels of the anti-apoptotic protein Bcl-2 (Khan et al. 2002), emphasise that programmed cell death is a balance between pro- and anti-apoptotic signals.”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Khan et al. 2002
CMV-specific CD8+ T cells in peripheral blood exhibit high levels of anti-apoptotic protein Bcl-2, which might render them insensitive to Fas-induced cell death.
“CMV-specific CD8+ T cells measured in peripheral blood have been shown to exhibit high levels of the anti-apoptotic protein Bcl-2 (Khan et al. 2002), which might render them insensitive to cell death induced the Fas-receptor (Fas-R) interacting with Fas-ligand (Fas-L).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Khan et al. 2002

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Authors: Khan, N., Shariff, N., Cobbold, M., Bruton, R., Ainsworth, J. A., Sinclair, A. J., Nayak, L., & Moss, P. A. H.
Affiliations: University of Birmingham (GB)
Cancer Research UK (GB)
Corresponding author: Khan, Naeem
Cobbold, Mark
Bruton, Rachel
ORCID: Khan, Naeem
Cobbold, Mark
Sinclair, Alan J
Moss, Paul A H
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2002-08
Volume: 169
Issue: 4
Pages: 1984-1992
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.169.4.1984
OpenAlex: W2115364134
Cited by: 754
References: 47
Citations by year: 2026: 13 · 2025: 17 · 2024: 17 · 2023: 20 · 2022: 25 · 2021: 23 · 2020: 26 · 2019: 30 · 2018: 29 · 2017: 42 · 2016: 39 · 2015: 37 · 2014: 29 · 2013: 40 · 2012: 34
FWCI: 26.13
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders: Medical Research Council
Topics: Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords: cytomegalovirus seropositivity, oligoclonal expansion, immunosenescence, older adults, effector memory T cells, T cell receptor repertoire, CD57, CCR7, CD28
MeSH terms: Aged, Aging, Amino Acid Sequence, Antibodies, Viral, Epitopes, Base Sequence, Clone Cells, Cytomegalovirus Infections, Cytomegalovirus, Humans, Immunologic Memory, Middle Aged, Oligopeptides, Phenotype, Phosphoproteins, T-Lymphocytes, Cytotoxic, Viral Matrix Proteins, DNA, Complementary, CD8-Positive T-Lymphocytes, Genes, T-Cell Receptor

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Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals

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