Multifunctional cytomegalovirus (CMV)‐specific CD8+ T cells are not restricted by telomere‐related senescence in young or old adults
Open accessAbstract
Summary: 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
For T cells in peripheral blood, there is a correlation between the sequential loss of costimulatory receptors on the cell surface and the progressive loss of telomeres.
“For T cells in peripheral blood, there is a correlation between the sequential loss of costimulatory receptors on the cell surface and the progressive loss of telomeres.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [54]
Flow-FISH has been refined to enable investigation of telomere length, surface phenotype and cytokine production in individual T cells within a mixed cell population.
“The flow-FISH technique has been refined to enable the investigation of telomere length, surface phenotype and cytokine production in individual T cells [54] within a mixed cell population.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [54]
Undifferentiated T cells with relatively long telomeres are CD27+CD28+, while senescent T cells with the shortest telomeres are found within the CD27-CD28- population.
“While undifferentiated T cells that have relatively long telomeres are CD27 + CD28 + , senescent T cells with the shortest telomeres are found within the CD27 - CD28 - population [22, 28, 34, 54].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [54]
Inflationary CD8+ cells, after proper activation stimuli, can divide, secrete cytokines, and execute cytolysis, i.e., they are not exhausted.
“Inflationary CD8+ cells, after proper activation stimuli, can divide, secrete cytokines, and execute cytolysis, i.e., they are not exhausted.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [52]
These inflated HCMV-specific memory T cells maintain their efficient effector functions for the lifetime of the individual.
“These inflated HCMV-specific memory T cells maintain their efficient effector functions for the lifetime of the individual (40, 46, 52).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [52]
These cells have telomeres of intermediate length, despite 'senescent' cell-surface characteristics (e.g., CD45RA+CD27−).
“In addition, these cells have telomeres of intermediate length, despite “senescent” cell-surface characteristics (e.g., CD45RA + CD27−) (Riddell et al. 2015).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Riddell et al. 2015
Many CMV-specific CD8+ T cells, identified using MHC-class I tetramers, are multifunctional, producing IFN-γ, IL-2 and TNF-α.
“Moreover, recent work has shown that many CMV-specific CD8+ T cells, identified using MHC-class I tetramers, are multifunctional, producing IFN-γ, IL-2 and TNF-α (Riddell et al. 2015).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Riddell et al. 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Caccamo, N., Guggino, G., Meraviglia, S., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005528 · Cited by 94 · see citing works
RetractedStructure and function of telomeres
Blackburn, E. H. (1991) · Nature · doi:10.1038/350569a0 · Cited by 3,596 · see citing works
Vigorous HIV-1-Specific CD4 + T Cell Responses Associated with Control of Viremia
Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M., Boswell, S. L., Sax, P. E., Kalams, S. A., & Walker, B. D. (1997) · Science · doi:10.1126/science.278.5342.1447 · Cited by 1,832 · see citing works
HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells
Betts, M. R. (2006) · Blood · doi:10.1182/blood-2005-12-4818 · Cited by 1,829 · see citing works
Association between telomere length in blood and mortality in people aged 60 years or older
Cawthon, R. M., Smith, K. R., O'Brien, E., Sivatchenko, A., & Kerber, R. A. (2003) · The Lancet · doi:10.1016/s0140-6736(03)12384-7 · Cited by 1,761 · see citing works
T-cell quality in memory and protection: implications for vaccine design
Seder, R. A., Darrah, P. A., & Roederer, M. (2008) · Nature reviews. Immunology · doi:10.1038/nri2274 · Cited by 1,541 · see citing works
Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection
Cannon, M. J., Schmid, D. S., & Hyde, T. B. (2010) · Reviews in Medical Virology · doi:10.1002/rmv.655 · Cited by 1,495 · see citing works
Phenotypic and functional separation of memory and effector human CD8+ T cells
Hamann, D., Baars, P. A., Rep, M. H. G., Hooibrink, B., Kerkhof-Garde, S. R., Klein, M. R., & Lier, R. A. W. V. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.9.1407 · Cited by 1,366 · see citing works
Feedback between p21 and reactive oxygen production is necessary for cell senescence
Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., et al. (2010) · Molecular Systems Biology · doi:10.1038/msb.2010.5 · Cited by 1,019 · see citing works
Phenotype and function of human T lymphocyte subsets: Consensus and issues
Appay, V., van Lier, R. A. W., Sallusto, F., & Roederer, M. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20643 · Cited by 729 · see citing works
Rufer, N., Brümmendorf, T. H., Kolvraa, S., Bischoff, C., Christensen, K., Wadsworth, L., Schulzer, M., & Lansdorp, P. M. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.2.157 · Cited by 709 · see citing works
Telomere shortening in atherosclerosis
Samani, N. J., Boultby, R., Butler, R., Thompson, J. R., & Goodall, A. H. (2001) · The Lancet · doi:10.1016/s0140-6736(01)05633-1 · Cited by 609 · see citing works
Geginat, J., Lanzavecchia, A., & Sallusto, F. (2003) · Blood · doi:10.1182/blood-2002-11-3577 · Cited by 604 · see citing works
Adoptive cell therapy for the treatment of patients with metastatic melanoma
Rosenberg, S. A., & Dudley, M. E. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.03.002 · Cited by 596 · see citing works
Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry
Rufer, N., Dragowska, W. H., Thornbury, G., Roosnek, E. E., & Lansdorp, P. M. (1998) · Nature Biotechnology · doi:10.1038/nbt0898-743 · Cited by 547 · see citing works
Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?
Akbar, A. N., & Henson, S. M. (2011) · Nature Reviews Immunology · doi:10.1038/nri2959 · Cited by 474 · see citing works
Self-citationAgeing and life-long maintenance of T-cell subsets in the face of latent persistent infections.
Nikolich-Žugich, J. (2008) · Nature reviews. Immunology · doi:10.1038/nri2318 · Cited by 463 · see citing works
Flow cytometry and FISH to measure the average length of telomeres (flow FISH)
Baerlocher, G. M., Vulto, I., de Jong, G., & Lansdorp, P. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.263 · Cited by 449 · see citing works
Regulated expression of telomerase activity in human T lymphocyte development and activation.
Weng, N., Levine, B. L., June, C. H., & Hodes, R. J. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.6.2471 · Cited by 403 · see citing works
p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells
Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75051 · Cited by 389 · see citing works
Self-citationThe roles of senescence and telomere shortening in cardiovascular disease
Fyhrquist, F., Saijonmaa, O. J., & Strandberg, T. E. (2013) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2013.30 · Cited by 368 · see citing works
Almanzar, G., Schwaiger, S., Jenewein, B., Keller, M., Herndler‐Brandstetter, D., Würzner, R., Schönitzer, D., & Grubeck‐Loebenstein, B. (2005) · Journal of Virology · doi:10.1128/jvi.79.6.3675-3683.2005 · Cited by 356 · see citing works
The role of CD8<sup>+</sup> T‐cell replicative senescence in human aging
Effros, R. B., Dagarag, M., Spaulding, C., & Man, J. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00259.x · Cited by 336 · see citing works
Zhou, J., Shen, X., Huang, J., Hodes, R. J., Rosenberg, S. A., & Robbins, P. F. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.10.7046 · Cited by 336 · see citing works
Hodes, R. J., Hathcock, K. S., & Weng, N. (2002) · Nature reviews. Immunology · doi:10.1038/nri890 · Cited by 315 · see citing works
Fletcher, J. M., Vukmanovic-Stejic, M., Dunne, P. J., Birch, K. E., Cook, J. E., Jackson, S. E., Salmon, M., Rustin, M. H., & Akbar, A. N. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.12.8218 · Cited by 296 · see citing works
Self-citationMillington, K. A., Innes, J. A., Hackforth, S., Hinks, T., Deeks, J. J., Dosanjh, D. P. S., Revol, V., Gunatheesan, R., Klenerman, P., & Lalvani, A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.5217 · Cited by 294 · see citing works
Chidrawar, S. M., Khan, N., Wei, W., McLarnon, A., Smith, N., Nayak, L., & Moss, P. A. H. (2009) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2008.03785.x · Cited by 244 · see citing works
Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells
Di Mitri, D., Azevedo, R. I., Henson, S. M., Libri, V., Riddell, N. E., Macaulay, R., Kipling, D., Soares, M. V. D., Battistini, L., & Akbar, A. N. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100978 · Cited by 231 · see citing works
Self-citationPreferential loss of IL‐2–secreting CD4+ T helper cells in chronic HCV infection†
Semmo, N., Day, C. L., Ward, S. M., Lucas, M., Harcourt, G., Loughry, A., & Klenerman, P. (2005) · Hepatology · doi:10.1002/hep.20669 · Cited by 186 · see citing works
Cytomegalovirus Infection Reduces Telomere Length of the Circulating T Cell Pool
van de Berg, P. J. E. J., Griffiths, S. J., Yong, S.-L., Macaulay, R., Bemelman, F. J., Jackson, S., Henson, S. M., ten Berge, I. J. M., Akbar, A. N., & van Lier, R. A. W. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903442 · Cited by 157 · see citing works
Self-citationBaerlocher, G. M., Mak, J., Tien, T., & Lansdorp, P. M. (2002) · Cytometry · doi:10.1002/cyto.10053 · Cited by 156 · see citing works
Cohen, S., Janicki‐Deverts, D., Turner, R. B., Casselbrant, M. L., Li‐Korotky, H., Epel, E. S., & Doyle, W. J. (2013) · JAMA · doi:10.1001/jama.2013.613 · Cited by 148 · see citing works
Will telomere erosion lead to a loss of T-cell memory?
Akbar, A. N., Beverley, P. C. L., & Salmon, M. (2004) · Nature Reviews Immunology · doi:10.1038/nri1440 · Cited by 135 · see citing works
Self-citationUncoupling T‐cell expansion from effector differentiation in cell‐based immunotherapy
Crompton, J. G., Sukumar, M., & Restifo, N. P. (2013) · Immunological Reviews · doi:10.1111/imr.12135 · Cited by 120 · see citing works
Immune senescence and vaccines to prevent herpes zoster in older persons
Levin, M. J. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.06.002 · Cited by 114 · see citing works
Reed, J. R., Vukmanovic-Stejic, M., Fletcher, J. M., Soares, M. V. D., Cook, J. E., Orteu, C. H., Jackson, S. E., Birch, K. E., Foster, G. R., Salmon, M., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040178 · Cited by 111 · see citing works
Self-citationLibri, V., Azevedo, R. I., Jackson, S. E., Di Mitri, D., Lachmann, R., Fuhrmann, S., Vukmanovic-Stejic, M., Yong, K., Battistini, L., Kern, F., et al. (2011) · Immunology · doi:10.1111/j.1365-2567.2010.03386.x · Cited by 111 · see citing works
Self-citationPlunkett, F. J., Soares, M. V. D., Annels, N. E., Hislop, A. D., Ivory, K., Lowdell, M. W., Salmon, M., Rickinson, A. B., & Akbar, A. N. (2001) · Blood · doi:10.1182/blood.v97.3.700 · Cited by 109 · see citing works
Self-citationAge-related deregulation of naive T cell homeostasis in elderly humans
Ferrando‐Martínez, S., Ruíz-Mateos, E., Hernández, A., Gutiérrez, E., Rodríguez-Méndez, M. M., Ordóñez, A., & Leal, M. (2010) · AGE · doi:10.1007/s11357-010-9170-8 · Cited by 109 · see citing works
Age-Associated Increase of Low-Avidity Cytomegalovirus-Specific CD8+ T Cells That Re-Express CD45RA
Griffiths, S. J., Riddell, N. E., Masters, J., Libri, V., Henson, S. M., Wertheimer, A., Wallace, D., Sims, S., Rivino, L., Larbi, A., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1203267 · Cited by 82 · see citing works
Self-citationWallace, D. L., Berard, M., Soares, M. V. D., Oldham, J. E., Cook, J. E., Akbar, A. N., Tough, D. F., & Beverley, P. C. L. (2006) · Immunology · doi:10.1111/j.1365-2567.2006.02429.x · Cited by 79 · see citing works
Self-citationPlunkett, F. J., Franzese, O., Belaramani, L. L., Fletcher, J. M., Gilmour, K. C., Sharifi, R., Khan, N., Hislop, A. D., Cara, A., Salmon, M., et al. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.006 · Cited by 74 · see citing works
Self-citationDunne, P. J. (2005) · Blood · doi:10.1182/blood-2004-11-4469 · Cited by 53 · see citing works
Kapoor, V., Hakim, F. T., Rehman, N., Gress, R. E., & Telford, W. G. (2009) · Journal of Immunological Methods · doi:10.1016/j.jim.2009.02.004 · Cited by 25 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [12]Montpetit AJ Alhareeri AA Montpetit M Telomere length: a review of methods for measurement Nurs Res 2014 63 289 99 24977726 PMC4292845
Cited by
Sorted by citations
Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C. M., Ligotti, M. E., Zareian, N., & Accardi, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02247 · Cited by 693 · see citing works
Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
Akbar, A. N., Henson, S. M., & Lanna, A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.09.002 · Cited by 285 · see citing works
Self-citationHuman memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses
Pulko, V., Davies, J. S., Martinez, C., Lanteri, M. C., Busch, M. P., Diamond, M. S., Knox, K., Bush, E. C., Sims, P. A., Sinari, S., et al. (2016) · Nature Immunology · doi:10.1038/ni.3483 · Cited by 175 · see citing works
Henson, S. M., Macaulay, R., Riddell, N. E., Nunn, C. J., & Akbar, A. N. (2015) · European Journal of Immunology · doi:10.1002/eji.201445312 · Cited by 146 · see citing works
Self-citationIs immunosenescence influenced by our lifetime “dose” of exercise?
Turner, J. E. (2016) · Biogerontology · doi:10.1007/s10522-016-9642-z · Cited by 112 · see citing works
Can blocking inflammation enhance immunity during aging?
Chambers, E. S., & Akbar, A. N. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.03.016 · Cited by 92 · see citing works
Self-citationKnown unknowns: how might the persistent herpesvirome shape immunity and aging?
Nikolich-Zugich, J., Goodrum, F., Knox, K., & Smithey, M. J. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.07.011 · Cited by 51 · see citing works
- Authors
- 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.
- Affiliations
- University College London (GB)
- National University of Singapore (SG)
- Division of Infection and Immunity University College London London UK
- Department of Immunology Hospital Reina Sofia University of Cordoba Cordoba Spain
- Hospital Universitario Reina Sofía (ES)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Akbar, Arne N.
- ORCID
- Venue
- Immunology
- Publisher
- Wiley
- Published
- 2015-03-09
- Volume
- 144
- Issue
- 4
- Pages
- 549-560
- ISSN
- 0019-2805 (ISSN-L)
- 1365-2567
- PMC
- PMC4368162
- OpenAlex
- W1969586306
- Cited by
- 60
- References
- 45
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 10 · 2017: 11 · 2016: 6 · 2015: 1
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- National University of Singapore (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Explore Bristol Research (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/L005336/1)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Keywords
- telomere length, cellular senescence, polyfunctional T cells, T cell differentiation, CD45RA, CD27, aging, replicative capacity, flow-FISH, interferon-gamma, interleukin-2, TNF-α
- MeSH terms
- Adult, Age Factors, Aged, Aged, 80 and over, Aging, Cell Differentiation, Cells, Cultured, Cytomegalovirus Infections, Cytomegalovirus, Flow Cytometry, Humans, London, Lymphocyte Activation, Phenotype, Singapore, Biomarkers, Immunophenotyping, Cytokines, Telomere, Cellular Senescence, Leukocyte Common Antigens, Tumor Necrosis Factor Receptor Superfamily, Member 7, CD8-Positive T-Lymphocytes, White People, Asian People, Cell Proliferation, Young Adult, Telomere Shortening
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
