The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation
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The enzyme telomerase is essential for maintaining the replicative capacity of memory T cells. Although CD28 costimulatory signals can up-regulate telomerase activity, human CD8(+) T cells lose CD28 expression after repeated activation. Nevertheless, telomerase is still inducible in CD8(+)CD28(-) T cells. To identify alternative costimulatory pathways that may be involved, we introduced chimeric receptors containing the signaling domains of CD28, CD27, CD137, CD134, and ICOS in series with the CD3 zeta (zeta) chain into primary human CD8(+) T cells. Although CD3 zeta-chain signals alone were ineffective, triggering of all the other constructs induced proliferation and telomerase activity. However, not all CD8(+)CD28(-) T cells could up-regulate this enzyme. The further fractionation of CD8(+)CD28(-) T cells into CD8(+)CD28(-) CD27(+) and CD8(+)CD28(-)CD27(-) subsets showed that the latter had significantly shorter telomeres and extremely poor telomerase activity. The restoration of CD28 signaling in CD8(+)CD28(-)CD27(-) T cells could not reverse the low telomerase activity that was not due to decreased expression of human telomerase reverse transcriptase, the enzyme catalytic subunit. Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity. Furthermore, the defective Akt phosphorylation in these cells was specific for the Ser(473) but not the Thr(308) phosphorylation site of this molecule. Telomerase down-regulation in highly differentiated CD8(+)CD28(-)CD27(-) T cells marks their inexorable progress toward a replicative end stage after activation. This limits the ability of memory CD8(+) T cells to be maintained by continuous proliferation in vivo.
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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 [22]
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 [22]
These T cells do not express the co-stimulatory molecule CD28, required for the activation of T cells.
“These T cells do not express the co-stimulatory molecule CD28, required for the activation of 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 [44]
The loss of CD28 occurs following cell proliferation, according to the observation that CD28− T cells have shorter telomeres than CD28+ cells.
“The loss of CD28 occurs following cell proliferation, according to the observation that the CD28− T cells have shorter telomeres than CD28+ cells.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [44]
Late-stage memory senescent T-cells may also acquire new functions, such as suppressive activity, as demonstrated in vitro.
“Late-stage memory senescent T-cells may also acquire new functions, such as suppressive activity, as demonstrated in vitro.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [44]
Senescent T cells are producers of pro-inflammatory cytokines.
“In addition, they are producers of pro-inflammatory cytokines (17, 18, 41–47).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [44]
CD28 seems a good biomarker of immunosenescence, as suggested by findings that late-differentiated CD8+/CD28− T cells tend to accumulate particularly in older people, frail or affected by age-related diseases.
“CD28 seems a good biomarker of immunosenescence, as further suggested by findings that late-differentiated CD8+/CD28− T cells tend to accumulate particularly in older people, frail or affected by age-related diseases.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [44]
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- Authors
- Plunkett, F. J., Franzese, O., Finney, H. M., Fletcher, J. M., Belaramani, L. L., Salmon, M., Dokal, I., Webster, D., Lawson, A. D. G., & Akbar, A. N.
- Affiliations
- University College London (GB)
- University of Rome Tor Vergata (IT)
- Celltech R&D , Slough, Berkshire ,
- University of Birmingham (GB)
- Queen Mary University of London (GB)
- The Royal Free Hospital (GB)
- Corresponding author
- Franzese, Ornella
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-06
- Volume
- 178
- Issue
- 12
- Pages
- 7710-7719
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1548372537
- Cited by
- 222
- References
- 55
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 15 · 2023: 9 · 2022: 19 · 2021: 17 · 2020: 12 · 2019: 8 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 7 · 2014: 13 · 2013: 7 · 2012: 8
- FWCI
- 9.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Biotechnology and Biological Sciences Research Council (BBS/B/04528, BB/E019188/1)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomerase activity, CD8+ T cells, CD28 costimulation, CD27, Akt phosphorylation, Ser473 phosphorylation, human telomerase reverse transcriptase, telomere length, memory T cells, replicative senescence, T cell differentiation
- MeSH terms
- Adult, Female, Humans, Immunologic Memory, Interleukin-2, Lymphocyte Activation, Male, Phosphorylation, Receptors, Immunologic, T-Lymphocyte Subsets, CD8 Antigens, CD28 Antigens, Tumor Necrosis Factor Receptor Superfamily, Member 7, CD8-Positive T-Lymphocytes, Telomerase, Interleukin-15, Proto-Oncogene Proteins c-akt
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.
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