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 and highly differentiated memory cells accumulate, often showing dysregulated properties.
“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]
Age-related functional changes in naive murine T cells are not caused by replication but by cellular longevity, which increases after thymectomy or in aged mice.
“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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Wang, W., Thomas, R. G., Sizova, O. S., & Su, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00773 · Cited by 63 · see citing works
“However, with age, BIM activation in T cells is declined and homeostatic immune rebalance is hindered, resulting in an accumulation of “exhausted” senescent T cells and pTreg cells (25, 26, 71, 72).”
BackgroundBim Dictates Naive CD4 T Cell Lifespan and the Development of Age-Associated Functional Defects
Tsukamoto, H., Huston, G. E., Dibble, J. P., Duso, D. K., & Swain, S. L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001668 · Cited by 57 · see citing works
Self-citationLongevity Factors and Mountain Water of Bulgaria in Factorial Research of Longevity
Ignatov, I., Mosin, O., & Velikov, B. (2014) · Journals & Books Hosting (International Knowledge Sharing Platform) · Cited by 56 · see citing works
Jones, S. C., Brahmakshatriya, V., Huston, G., Dibble, J., & Swain, S. L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901296 · Cited by 54 · see citing works
“However, effectors “rescued” by exogenous IL-2 did not become functional memory CD4 T cells (13, 21).”
BackgroundSelf-citationLongevity Factors and Mountain Water as a Factor Research in Mountain and Field Areas in Bulgaria
Ignatov, I., Mosin, O., Velikov, B., Bauer, E., & Tyminski, G. (2014) · Civil and environmental research · Cited by 54 · see citing works
Tsukamoto, H., Fujieda, K., Hirayama, M., Ikeda, T., Yuno, A., Matsumura, K., Fukuma, D., Araki, K., Mizuta, H., Nakayama, H., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2446 · Cited by 53 · see citing works
Self-citationHaegert, D. G., Hackenbroch, J., Duszczyszyn, D. A., Fitz-Gerald, L., Zastepa, E., Mason, H., Lapierre, Y., Antel, J. P., & Bar‐Or, A. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.12.007 · Cited by 52 · see citing works
“In this regard, a murine study shows that increased naïve T-cell longevity, associated with reduced thymic output, impairs naïve CD4 T-cell functioning with reduced proliferation and IL-2 production in response to antigen (Tsukamoto et al., 2009).”
BackgroundHIV RNA Suppression and Immune Restoration: Can We Do Better?
Pinzone, M. R., Rosa, M. D., Cacopardo, B. S., & Nunnari, G. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/515962 · Cited by 52 · see citing works
Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly
Wang, W., Thomas, R. G., Oh, J., & Su, D. (2021) · Cells · doi:10.3390/cells10030628 · Cited by 52 · see citing works
“However, it is also well established that pTreg cells accumulate with age and this abnormal accumulation has been implicated in immunosuppression of anti-infection and anti-tumor immunity, and inhibition of vaccination efficacy in the elderly [56,57,79].”
BackgroundInflammation Enhances IL-2 Driven Differentiation of Cytolytic CD4 T Cells
Workman, A. M., Jacobs, A., Vogel, A. J., Condon, S. A., & Brown, D. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089010 · Cited by 49 · see citing works
“At various time points, cells were collected and stained with anti-CD4, anti-TCR (KJ126) and anti-CD44, followed by intracellular staining for phosphorylated STAT5 using antiSTAT5 (pY694) from BDBiosciences (San Diego, CA) as described in [54].”
MethodCD4 T cell defects in the aged: Causes, consequences and strategies to circumvent
Zhang, W., Brahmakshatriya, V., & Swain, S. L. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.002 · Cited by 49 · see citing works
“, 2009, 2010), and in humans undergo increased homeostatic division (Nikolich-Zugich, 2012), both of which cause them to progressively develop intrinsic changes that reduce their response to antigen (Tsukamoto et al., 2009).”
BackgroundSelf-citationComparison of the Sensitivity of QuantiFERON-TB Gold In-Tube and T-SPOT.TB According to Patient Age
Bae, W. C., Park, K. U., Song, E. Y., Kim, S. J., Lee, Y. J., Park, J. S., Cho, Y., Yoon, H. I., Yim, J., Lee, C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0156917 · Cited by 48 · see citing works
“Since aging leads to a decline in the strength of immune responses [6, 7], older individuals tend to be more susceptible to TB [8].”
BackgroundBrahmakshatriya, V., Kuang, Y., Devarajan, P., Xia, J., Zhang, W., Vong, A. M., & Swain, S. L. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601119 · Cited by 43 · see citing works
“In addition, the generation of T and B cell memory from aged naive cells is highly compromised (15, 16).”
BackgroundSelf-citationIgnatov, I., Mosin, O., Velikov, B., Bauer, E., & Tyminski, G. (2014) · Journals & Books Hosting (International Knowledge Sharing Platform) · Cited by 40 · see citing works
Rane, S., Hogan, T. V., Seddon, B. P., & Yates, A. J. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2003949 · Cited by 40 · see citing works
Al-Chami, E., Tormo, A. J., Pasquin, S., Kanjarawi, R., Ziouani, S., & Rafei, M. (2016) · Aging Cell · doi:10.1111/acel.12440 · Cited by 39 · see citing works
“Repeated observations revealed that beside scarcity of T-cell precursors in the pre-immune repertoire, IL-2 production, cell surface expression of CD25, and T-cell proliferation are all greatly reduced in ageing hosts (Haynes & Swain, 2006; Maue et al., 2009; Tsukamoto et al., 2009).”
BackgroundInfluentialAging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients
Al-Danakh, A. Y., Safi, M., Jian, Y., Yang, L., Zhu, X., Chen, Q., Yang, K., Wang, S., Zhang, J., & Yang, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1348189 · Cited by 36 · see citing works
Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging
Coder, B., Wang, W., Wang, L., Wu, Z., Zhuge, Q., & Su, D. (2016) · Oncotarget · doi:10.18632/oncotarget.12572 · Cited by 35 · see citing works
“The immune periphery of aged animals and humans have an accumulation of Tregs [40], resulting from a decrease in pro-apoptotic Bim gene expression [188-190].”
BackgroundT-cell immunity in the aging human
Pawelec, G. (2014) · Haematologica · doi:10.3324/haematol.2013.094383 · Cited by 36 · see citing works
“mice, they have been exposed to the aged mouse environment over its lifetime.(14) The conclusion from experiments of this type is that such old cells are functionally compro-”
BackgroundIgnatov, I., Mosin, O., Velikov, B., Bauer, E., & Tyminski, G. (2014) · European Journal of Molecular Biotechnology · doi:10.13187/ejmb.2014.4.52 · Cited by 35 · see citing works
Fate mapping reveals the age structure of the peripheral T cell compartment
Reynaldi, A., Smith, N. L., Schlub, T. E., Tabilas, C., Venturi, V., Rudd, B. D., & Davenport, M. P. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811634116 · Cited by 34 · see citing works
“Previous work analyzing immune cell survival has often relied on proliferation labels to measure cell division and death rates to predict cell survival, analysis of cell replacement after bone marrow transplantation, or adoptive transfer of cells into new hosts (5, 8, 10, 11).”
BackgroundMethodResultInfluentialThe impact of aging on CD4+ T cell responses to influenza infection
Lorenzo, E. C., Bartley, J. M., & Haynes, L. (2018) · Biogerontology · doi:10.1007/s10522-018-9754-8 · Cited by 33 · see citing works
“Although this contributes to overall CD4 + T cell homeostasis, longer lived naïve CD4 + T cells demonstrate functional defects including reduced proliferation and IL-2 production (Tsukamoto et al. 2009).”
Self-citationThe natural history of naive T cells from birth to maturity
Seddon, B. P., & Yates, A. J. (2018) · Immunological Reviews · doi:10.1111/imr.12694 · Cited by 33 · see citing works
Age-related Deficiencies in Antigen-Specific CD4 T cell Responses: Lessons from Mouse Models.
Haynes, L., & Lefebvre, J. S. (2011) · Europe PMC (PubMed Central) · Cited by 33 · see citing works
Self-citationPhenotype and functions of conventional dendritic cells are not compromised in aged mice
Tan, S., Cavanagh, L. L., d'Advigor, W., Shackel, N. A., Groth, B. F. D. S., & Weninger, W. (2012) · Immunology and Cell Biology · doi:10.1038/icb.2011.104 · Cited by 32 · see citing works
Gigley, J. P., & Khan, I. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020838 · Cited by 31 · see citing works
“[26,27,28].”
TRIB2 safeguards naive T cell homeostasis during aging
Cao, W., Sturmlechner, I., Zhang, H., Jin, J., Hu, B., Jadhav, R. R., Fang, F., Weyand, C. M., & Goronzy, J. J. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112195 · Cited by 30 · see citing works
MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function
Grewers, Z., & Krueger, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176200 · Cited by 30 · see citing works
“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”
BackgroundDavies, J. S., Thompson, H. L., Pulko, V., Padilla‐Torres, J., & Nikolich‐Žugich, J. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx102 · Cited by 30 · see citing works
“in wild type, old and adult thymectomized mice (34,40), although the extent of peripheral selection in thymectomized mice has not been formally established in that study.”
The paradox of aging: Aging-related shifts in T cell function and metabolism
Quinn, K. M., Moreno-Vicencio, D., & Gruta, N. L. L. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101834 · Cited by 28 · see citing works
Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients
Xiang, F., Chen, R., Cao, X., Shen, B., Chen, X., Ding, X., & Zou, J. (2020) · BMC Nephrology · doi:10.1186/s12882-020-01920-8 · Cited by 29 · see citing works
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 · see citing works
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 · see citing works
“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, E. H., Glukhovskiy, P., & Pishel, I. (2014) · BioResearch open access · doi:10.1089/biores.2014.0043 · Cited by 24 · see citing works
Xie, Y., Sun, J. M., Hu, C., Ruan, B., & Zhu, B. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.794746 · Cited by 27 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
de Boer, R. J., & Yates, A. J. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-040924 · Cited by 24 · see citing works
“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 · see citing works
“(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 23 · see citing works
“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., & Callard, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0049554 · Cited by 23 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 20 · see citing works
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 19 · see citing works
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 18 · see citing works
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 · see citing works
“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 · see citing works
“(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 · see citing works
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 14 · see citing works
“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 15 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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
- 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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