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

Natalie E Riddell, Stephen J Griffiths, Laura Rivino, David C B King, Guo H Teo, Sian M Henson, Sara Cantisan, Rafael Solana, David M Kemeny, Paul A MacAry, Anis Larbi, Arne N Akbar

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

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.

Original languageEnglish
Pages (from-to)549-60
Number of pages12
JournalImmunology
Volume144
Issue number4
DOIs
Publication statusPublished - Apr 2015

Bibliographical note

© 2014 The Authors. Immunology published by John Wiley & Sons Ltd.

Keywords

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Aging/ethnology
  • Asian Continental Ancestry Group/genetics
  • Biomarkers/metabolism
  • CD8-Positive T-Lymphocytes/immunology
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence
  • Cytokines/immunology
  • Cytomegalovirus/immunology
  • Cytomegalovirus Infections/genetics
  • European Continental Ancestry Group/genetics
  • Flow Cytometry
  • Humans
  • Immunophenotyping/methods
  • Leukocyte Common Antigens/immunology
  • London
  • Lymphocyte Activation
  • Phenotype
  • Singapore
  • Telomere/genetics
  • Telomere Shortening
  • Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
  • Young Adult

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