David Colin Bruce King

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lsidcbk@nus.edu.sg


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    Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults
    (Blackwell Publishing Ltd, 2015) Riddell, N.E; Griffiths, S.J; Rivino, L; King, D.C.B; Teo, G.H; Henson, S.M; Cantisan, S; Solana, R; Kemeny, D.M; Macary, P.A; Larbi, A; Akbar, A.N; MICROBIOLOGY AND IMMUNOLOGY; LIFE SCIENCES INSTITUTE; DUKE-NUS MEDICAL SCHOOL
    Summary: Antigen-specific multifunctional T cells that secrete interferon-?, interleukin-2 and tumour necrosis factor-? 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-?, interleukin-2 and tumour necrosis factor-? are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion. © 2014 The Authors. Immunology published by John Wiley & Sons Ltd.