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Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects
Open accessAbstract
With age, T-cell generation from the thymus is much reduced, yet a substantial naïve T-cell pool is maintained even in aged animals, suggesting that naïve T cells either persist longer or turn over faster to maintain T-cell homeostasis. We found that with age, naïve CD4 T cells became progressively longer-lived. Their longer lifespan did not depend on recognition of self-peptide/class II. Newly generated naïve T cells derived from aged stem cells had a shorter lifespan, like that of young naïve T cells. Conversely, naïve CD4 T cells derived from middle-aged thymectomized mice were longer-lived in vivo, and their development of functional defects was accelerated. These observations suggest that naïve T cells develop their longer lifespan during their sojourn in the periphery. Increased longevity of naïve CD4 T cells correlated well with reduced expression of proapoptotic molecule Bim. We suggest that the intrinsic increase in longevity helps maintain naïve T-cell homeostasis but facilitates the development of functional defects in mice.
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“With aging, the naïve subset shrinks along with the accumulation of highly differentiated memory cells, which often show dysregulated properties (5, 6).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [6]
In the citing paper
“Age-associated functional changes in naive murine T cells are not a consequence of replication—they at most divide once throughout life—but are a corollary of cellular longevity that even increases after thymectomy or in aged mice”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Tsukamoto et al., 2009
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Tsukamoto, H., Senju, S., Matsumura, K., Swain, S. L., & Nishimura, Y. (2015) · Nature Communications · doi:10.1038/ncomms7702 · Cited by 104
Self-citationHematopoietic progenitor migration to the adult thymus
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BackgroundMethodResultInfluentialThe impact of aging on CD4+ T cell responses to influenza infection
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TRIB2 safeguards naive T cell homeostasis during aging
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“Thus, long-lived naive CD4 T cells produced less IL-2 in mice [87], and in humans, naive CD4 T cells from aged individuals were”
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Epidemiology of Tuberculosis Immunology
Fox, G. J., & Menzies, D. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-6111-1_1 · Cited by 28
Chen, J., Titanji, K., Sheth, A. N., Gandhi, R. T., McMahon, D. K., Ofotokun, I., Weitzmann, M. N., Paris, K. D., & Dumond, J. B. (2022) · Immunity & Ageing · doi:10.1186/s12979-021-00260-x · Cited by 28
“As a potential off-setting effect, aging could extend the half-life of naïve T-cells [9].”
BackgroundAged Mice Repeatedly Injected with Plasma from Young Mice: A Survival Study
Shytikov, D. W., Balva, O., Debonneuil, É., Glukhovskiy, P., & Pishel, I. (2014) · BioResearch open access · doi:10.1089/biores.2014.0043 · Cited by 26
Xie, Y., Sun, J. M., Hu, C., Ruan, B., & Zhu, B. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.794746 · Cited by 27
Vaccine-Induced Boosting of Influenza Virus-Specific CD4 T Cells in Younger and Aged Humans
Dolfi, D. V., Mansfield, K. D., Kurupati, R. K., Kannan, S., Doyle, S. A., Ertl, H. C. J., Schmader, K. E., & Wherry, E. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077164 · Cited by 26
“However, an increase in senescent T cells in the aged [8,18] could lead to decreased survival following boost.”
BackgroundImmunological biomarkers of aging
Wu, F., Mu, W., Markov, N. T., Fuentealba, M., Halaweh, H., Senchyna, F., Manwaring-Mueller, M., Winer, D. A., & Furman, D. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkae036 · Cited by 28
“123,124 Inappropriate activation of aged CD4 þ T cells leads to aberrant and incomplete differentiation of T helper 1 and 2 effector cells, resulting in an imbalanced subset of different T helper cells in mice with a skew toward T helper 17 cells, driving inflammaging and autoimmunity.”
Convergence and divergence of individual immune responses over the life course
Metcalf, C. J. E., Graham, A. L., Yates, A. J., & Cummings, D. A. T. (2025) · Science · doi:10.1126/science.ady9543 · Cited by 26
Towards a unified model of naive T cell dynamics across the lifespan
Rane, S., Hogan, T. V., Lee, E. S., Seddon, B. P., & Yates, A. J. (2022) · eLife · doi:10.7554/elife.78168 · Cited by 26
de Boer, R. J., & Yates, A. J. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-040924 · Cited by 29
“The ability of older naive T cells to persist longer than younger ones is consistent with other experimental studies (18, 19) and can also explain the slowing kinetic of loss of naive T cells following thymectomy, which has also been ascribed to a density-dependent regulation of cell numbers (20).”
ResultHung, L., Huang, K., Yang, D., Chang, D., Lai, J., & Ho, L. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.09.005 · Cited by 24
“(Tsukamoto et al., 2009) demonstrated that in a transgenic mice model, after thymectomy that prevents de novo production of T cells, the half-life of aged naı̈ve T cells is about 3-fold longer than that of young cells and such an increased longevity appears to correlate with reduced expression of a pro-apoptotic molec…”
BackgroundEstablishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment
Silva, S. L., & Sousa, A. E. (2016) · Frontiers in Pediatrics · doi:10.3389/fped.2016.00119 · Cited by 26
“An increase in the peripheral survival of naïve CD4+ T-cells in the elderly has been predicted by in silico models, in agreement with experimental data in mice (118).”
ResultHeterogeneity in Thymic Emigrants: Implications for Thymectomy and Immunosenescence
Bains, I., Yates, A. J., & Callard, R. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0049554 · Cited by 25
Kim, K., Yi, J., & Lee, S. H. (2015) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2015.30.5.705 · Cited by 22
“During the latter two phases, mostly naïve CD4 T cells increase by various mechanisms: de novo production of T cells in the thymus, homeostatic proliferation of residual CD4 T cells, and the extension of the half-life of CD4 T cells [2,11].”
BackgroundHow to Define Biomarkers of Human T Cell Aging and Immunocompetence?
Herndler‐Brandstetter, D., Ishigame, H., & Flavell, R. A. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00136 · Cited by 22
“Yet, aged naïve CD4+ T cells respond with an unimpaired IL-2 production upon stimulation with neoantigen and major signaling defects, such as the lack of calcium influx observed in aged mouse naïve T cells, are not seen in humans (Gomez et al., 2004; Tsukamoto et al., 2009).”
BackgroundAge- and sex-associated differences in immune cell populations
Gheitasi, R., Baumgart, S., Roell, D., Rose, N., Watzl, C., Dudziak, D., Andreas, N., Makarewicz, O., Drube, S., Schnizer, C., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113092 · Cited by 20
“30 In line with previous findings, 7,33 our results confirm this sex-specific pattern.”
Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19
Alsalman, A., Al-Mterin, M. A., & Elkord, E. (2022) · Journal of Immunology Research · doi:10.1155/2022/5545319 · Cited by 22
Better safe than sorry: Naive T-cell dynamics in healthy ageing
de Boer, R. J., Tesselaar, K., & Borghans, J. A. M. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101839 · Cited by 20
Metabolic syndrome, hormones, and maintenance of T cells during aging
Hsu, H., & Mountz, J. D. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.05.002 · Cited by 17
Immune Checkpoint Inhibitors in Geriatric Oncology
Cook, S. L., Amin, M. A., Bari, S., Poonnen, P. J., Khasraw, M., & Johnson, M. O. (2024) · Current Oncology Reports · doi:10.1007/s11912-024-01528-3 · Cited by 18
“In order to maintain a naïve T cell pool, aged T cells can persist longer than young T cells, but this is not due to increased proliferation of the naïve cells, but rather a reduction in apoptosis [17, 18].”
Dynamics of Recent Thymic Emigrants in Young Adult Mice
van Hoeven, V., Drylewicz, J., Westera, L., den Braber, I., Mugwagwa, T., Tesselaar, K., Borghans, J. A. M., & de Boer, R. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00933 · Cited by 16
“(9) were isolated from 5-week-old mice and the MN T cells from mice that were at least 12weeks old, it has been suggested that the observed differences in dynamic behavior between CD4+ RTE and MN T cells may in fact have been caused by the different ages of the donor mice (10, 11, 32).”
BackgroundIgnatov, I., Mosin, O., Velikov, B., & Bauer, E. (2014) · Journal of Medicine, Physiology and Biophysics · Cited by 14
Transcriptomic profiles of aging in naïve and memory CD4+ cells from mice
Taylor, J. R., Reynolds, L. M., Hou, L., Lohman, K., Cui, W., Kritchevsky, S. B., McCall, C. E., & Liu, Y. (2017) · Immunity & Ageing · doi:10.1186/s12979-017-0092-5 · Cited by 17
“The role of apoptosis in aging T cells appears complex; some studies report an age-related increase in apoptosis [6, 39] while others report an age-related impairment of apoptosis [7, 40].”
InfluentialDevarajan, P., Jones, M. C., Kugler‐Umana, O., Vong, A. M., Xia, J., & Swain, S. L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00596 · Cited by 16
“The number of naive T cells (50) and naive follicular B cells (FOB) decreases and remaining naive cells are less responsive (51).”
BackgroundSelf-citationIgnatov, I., Mosin, O., & Velikov, B. (2015) · Journals & Books Hosting (International Knowledge Sharing Platform) · Cited by 12
Dysregulated Th1 cells in lung squamous cell carcinoma
Wang, J., Zhou, J., Zhou, Q., Qi, Y., Zhang, P., Yan, C., & Ren, X. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ma0422-208r · Cited by 11
Bullock, M. E., Hogan, T. V., Williams, C., Morris, S. E., Nowicka, M., Sharjeel, M., van Dorp, C. H., Yates, A. J., & Seddon, B. P. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002380 · Cited by 10
“This behaviour mirrors that of naive CD4 and CD8 T cells that we and others have identified in both mice [27,28,36] and humans [37], suggesting it is an intrinsic property of T cells.”
Result
Metadata
- Authors
- Tsukamoto, H., Clise-Dwyer, K., Huston, G. E., Duso, D. K., Buck, A. L., Johnson, L. L., Haynes, L., & Swain, S. L.
- Affiliations
- Trudeau Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-10-27
- Volume
- 106
- Issue
- 43
- Pages
- 18333-18338
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2759371
- OpenAlex
- W2137105060
- Cited by
- 166
- References
- 47
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 21 · 2020: 8 · 2019: 2 · 2018: 7 · 2017: 14 · 2016: 9 · 2015: 15 · 2014: 16 · 2013: 12 · 2012: 11
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG021600)
- National Institute on Aging (P01AG021600, R37AG025805, AG021600, AG025805)
- Topics
- 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
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- naive CD4+ T cells, T cell lifespan, aging, T cell homeostasis, thymic output, thymectomy, building information modeling, apoptosis, periphery
- MeSH terms
- Bcl-2-Like Protein 11, Aging, Animals, Cell Survival, Histocompatibility Antigens, Homeostasis, Immunity, Innate, Membrane Proteins, Proto-Oncogene Proteins, Receptors, Antigen, T-Cell, T-Lymphocytes, Thymectomy, Signal Transduction, CD4-Positive T-Lymphocytes, Apoptosis Regulatory Proteins, Mice
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