IFN-α Inhibits Telomerase in Human CD8+ T Cells by Both hTERT Downregulation and Induction of p38 MAPK Signaling
Open accessAbstract
The cytokine IFN-α is secreted during viral infections and has been shown to inhibit telomerase activity and accelerate T cell differentiation in vivo. However, the mechanism for this inhibition is not clear. In this study, we show that IFN-α inhibits both the transcription and translation of human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, in activated CD8+ T cells. This was associated with increased activity of the repressor of hTERT transcription E2 transcription factor and decreased activation of NF-κB that promotes hTERT transcription. However IFN-α did not affect the translocation of hTERT from the cytoplasm to the nucleus. IFN-α also inhibits AKT kinase activation but increases p38 MAPK activity, and both of these events have been shown previously to inhibit telomerase activity. Addition of BIRB796, an inhibitor of p38 activity, to IFN-α–treated cells reversed, in part, the inhibition of telomerase by this cytokine. Therefore, IFN-α can inhibit the enzyme telomerase in CD8+ T cells by transcriptional and posttranslational mechanisms. Furthermore, the addition of IFN-α to CD8+CD27+CD28+ T cells accelerates the loss of both these costimulatory molecules. This suggests that persistent viral infections may contribute to the accumulation of highly differentiated/senescent CD8+CD27−CD28− T cells during aging by promoting IFN-α secretion during repeated episodes of viral reactivation.
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Within primary human T cells, both CD4+ and CD8+ populations contain a subset of poorly proliferative cells with characteristics very similar to senescent fibroblasts.
“Within primary human T cells, in both CD4 + [23, 28, 29] and CD8 + [25, 30] populations, there is a subset of poorly proliferative cells that exhibit characteristics that are very similar to senescent fibroblasts (Fig. 1).”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [29]
Inflammatory cytokines such as IFN-alpha can activate p38 in non-senescent T cells and inhibit proliferation and telomerase activity.
“In this context, inflammatory cytokines such as IFN- , can activate p38 in non-senescent T cells and this can inhibit proliferation and telomerase activity [29, 34, 61].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [29]
Inflammatory cytokines such as IFN-alpha can inhibit telomerase in T cells and induce telomere erosion, which lends support to the possibility that short telomeres are a secondary consequence of chronic systemic inflammation.
“The fact that inflammatory cytokines such as IFN can inhibit telomerase in T cells and induce telomere erosion in these cells [29, 34, 61] lends support to the latter possibility.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [29]
There is an interrelationship between senescence, nutrition and inflammation in regulating T cell function.
“the new awareness of the interrelationship between senescence, nutrition and inflammation in regulating T cell function [25, 29, 61].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [29]
IFN-α signal can activate p38, triggering cellular senescence, and leading to inhibition of proliferation and telomerase activity in non-senescent T cells.
“However, IFN-α signal can activate p38, triggering cellular senescence, and leading to inhibition of proliferation and telomerase activity in non-senescent T cells (189).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [189]
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- Authors
- Lanna, A., Coutavas, E., Levati, L., Seidel, J., Rustin, M. H. A., Henson, S. M., Akbar, A. N., & Franzese, O.
- Affiliations
- University of Rome Tor Vergata (IT)
- Howard Hughes Medical Institute (US)
- Istituto Dermopatico dell'Immacolata (IT)
- University College London (GB)
- The Royal Free Hospital (GB)
- Division of Infection and Immunity, University College London , London WC1E 6JF,
- Corresponding author
- Lanna, Alessio
- Franzese, Ornella
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-10-01
- Volume
- 191
- Issue
- 7
- Pages
- 3744-3752
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3836248
- OpenAlex
- W2131280544
- Cited by
- 62
- References
- 62
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 5 · 2015: 3 · 2014: 2 · 2012: 1
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Funders
- Alleanza Contro il Cancro
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BBS/B/04528, BB/J006750/1)
- 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
- interferon-alpha, telomerase, hTERT, CD8+ T cells, p38 MAPK, NF-κB, Akt signaling, T cell senescence, CD27, CD28, costimulatory molecules, viral reactivation, aging, post-translational regulation
- MeSH terms
- Cells, Cultured, Enzyme Activation, Humans, Lymphocyte Activation, Transcription, Genetic, Signal Transduction, Down-Regulation, NF-kappa B, Interferon-alpha, CD28 Antigens, Tumor Necrosis Factor Receptor Superfamily, Member 7, CD8-Positive T-Lymphocytes, Telomerase, p38 Mitogen-Activated Protein Kinases, E2F Transcription Factors, Proto-Oncogene Proteins c-akt
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