title: Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.
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.
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Riddell
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Griffiths
authors.forename: Laura
authors.initials: L
authors.lastname: Rivino
authors.forename: David C B
authors.initials: DC
authors.lastname: King
authors.forename: Guo H
authors.initials: GH
authors.lastname: Teo
authors.forename: Sian M
authors.initials: SM
authors.lastname: Henson
authors.forename: Sara
authors.initials: S
authors.lastname: Cantisan
authors.forename: Rafael
authors.initials: R
authors.lastname: Solana
authors.forename: David M
authors.initials: DM
authors.lastname: Kemeny
authors.forename: Paul A
authors.initials: PA
authors.lastname: MacAry
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000208:ethnology / Q000235:genetics / Q000276:immunology*; D044466:Asian People / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008131:London; D008213:Lymphocyte Activation; D010641:Phenotype; D012846:Singapore; D016615:Telomere / Q000235:genetics / Q000276:immunology*; D059506:Telomere Shortening; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D017493:Leukocyte Common Antigens
keywords: CD8+ T cells; cytomegalovirus; multi-functional; senescence; telomere