The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome
Abstract
Patients with X-linked lymphoproliferative syndrome (XLP) experience excessive T cell proliferation after primary Epstein-Barr virus (EBV) infection, due to mutations in the signalling lymphocyte activation molecule (SLAM) associated protein (SAP) molecule. We examined the impact of dysfunctional proliferative control on the extent of CD8+ T cell differentiation in XLP patients who recovered from primary EBV infection. Although these young patients have normal numbers of lytic and latent EBV-epitope-specific CD8+ T cells, they were extremely differentiated as defined by loss of CCR7 and CD27, low telomerase activity and very short telomeres. This was not a direct effect arising from the loss of SAP, but was due to excessive T cell stimulation due to this defect. Thus, transduction of XLP CD8+ T cells with the catalytic component of telomerase (hTERT), but not SAP, prevented telomere loss and considerably extended proliferative lifespan in vitro. These results indicate that excessive proliferation in CD8+ T cells in XLP patients may lead to end-stage differentiation and loss of functional EBV-specific CD8+ T cells through replicative senescence. This may contribute to the defective immunity found in XLP patients who survive acute EBV infection who develop EBV-related B cell lymphomas before the fourth decade of life.
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Cellular senescence can occur independently of telomere attrition when actual DNA damage anywhere in the genome activates a brake on cellular proliferation.
“Cellular senescence can also result independently of telomere attrition, when there is actual damage to DNA that can occur anywhere in the genome and this also activates a brake on cellular proliferation [13, 14].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [13]
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- Authors
- Plunkett, F. J., Franzese, O., Belaramani, L. L., Fletcher, J. M., Gilmour, K. C., Sharifi, R., Khan, N., Hislop, A. D., Cara, A., Salmon, M., Gaspar, H. B., Rustin, M. H. A., Webster, D., & Akbar, A. N.
- Affiliations
- The Royal Free Hospital (GB)
- University of Rome Tor Vergata (IT)
- National Health Service (GB)
- University College London (GB)
- University of Birmingham (GB)
- Istituto Superiore di Sanità (IT)
- Corresponding author
- Akbar, Arne N.
- ORCID
- Venue
- Mechanisms of Ageing and Development
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 126
- Issue
- 8
- Pages
- 855-865
- ISSN
- 0047-6374 (ISSN-L)
- OpenAlex
- W2057432053
- Cited by
- 74
- References
- 9
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 9 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 5 · 2012: 4
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mechanisms of Ageing and Development (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)
- Funders
- Istituto Superiore di Sanità
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- X-linked lymphoproliferative disease, telomere shortening, CD8+ T cells, replicative senescence, Epstein-Barr virus, T cell proliferation, telomerase, hTERT, SAP, CCR7, CD27, EBV-specific T cells, T cell differentiation
- MeSH terms
- Adult, Age Factors, Aged, Aged, 80 and over, Epitopes, Cell Differentiation, Cell Line, DNA-Binding Proteins, Flow Cytometry, Genetic Vectors, Humans, Immunologic Memory, Longevity, Lymphoproliferative Disorders, Mutation, Phenotype, Retroviridae, T-Lymphocytes, Time Factors, Lentivirus, Lymphoma, B-Cell, Telomere, CD8-Positive T-Lymphocytes, Telomerase, Cell Proliferation, Green Fluorescent Proteins
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