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Maintenance of Peripheral Naive T Cells Is Sustained by Thymus Output in Mice but Not Humans
Open accessAbstract
Parallels between T cell kinetics in mice and men have fueled the idea that a young mouse is a good model system for a young human, and an old mouse, for an elderly human. By combining in vivo kinetic labeling using deuterated water, thymectomy experiments, analysis of T cell receptor excision circles and CD31 expression, and mathematical modeling, we have quantified the contribution of thymus output and peripheral naive T cell division to the maintenance of T cells in mice and men. Aging affected naive T cell maintenance fundamentally differently in mice and men. Whereas the naive T cell pool in mice was almost exclusively sustained by thymus output throughout their lifetime, the maintenance of the adult human naive T cell pool occurred almost exclusively through peripheral T cell division. These findings put constraints on the extrapolation of insights into T cell dynamics from mouse to man and vice versa.
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“Naive murine T cells survive for only 30 days, while cell divisions from homeostatic proliferation occur only every 1 to 2 years”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as den Braber et al., 2012
In the citing paper
“T cell generation during human adult life depends on peripheral proliferation of naive T cells”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as den Braber et al., 2012
In the citing paper
“the number of divisions appears to be lower than what is required to generate 10,000 descendants. Frequencies of TCR excision circles (TRECs) that form during TCR-α rearrangement are more consistent with clonal sizes of around 100 cells”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as den Braber et al., 2012
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Self-citationEffect of cellular aging on memory T-cell homeostasis
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“Because TRECs do not replicate during cellular proliferation in the periphery, the TREC content of T cell populations correlates with thymic output assuming TRECs are stable. den Braber et al. (2012) measure the average TREC content in naive T cells of both mice and humans.”
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“In contrast to humans where they dominantly overtake the T cell pool in aging, the impact of CD8 TRM expansion in mice is offset by compensatory factors including continual production of new T cells by the thymus (Clambey et al., 2005; den Braber et al., 2012).”
BackgroundResultInfluentialT Cell Subsets and Immune Homeostasis
Wu, C., Jiang, M., Pang, T., & Zhang, C. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3754-8_3 · Cited by 9
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“Given aging leads to delayed wound healing, increased susceptibility to infection, loss of muscle quality, and chronic inflammation called inflammaging, 25,26 it may be difficult for older people to improve their cachexia even after tumor removal.”
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PREX1 improves homeostatic proliferation to maintain a naive CD4+ T cell compartment in older age
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“JCI Insight 2024;9(5):e172848 https://doi.org/10.1172/jci.insight.172848 Thymic T cell generation and peripheral T cell survival are more important in the mouse versus homeostatic proliferation in humans (9, 41).”
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Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling
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“This phenomenon occurs especially in the T-cell compartment and is caused by thymus involution [7-12].”
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Measuring thymic output across the human lifespan: a critical challenge in laboratory medicine
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“Moreover, humans rely primarily on homeostatic proliferation to maintain the naïve T cell pool [13], and age-associated thymic atrophy is far more pronounced in humans than in mice [14].”
Metabolic Signaling as a Driver of T Cell Aging
Choi, M. S., Choi, S., Cho, M., & Kim, C. (2025) · Immune Network · doi:10.4110/in.2025.25.e14 · Cited by 8
Sustained mTORC1 activation in activated T cells impairs vaccine responses in older individuals
Lin, X., Du, Y., Kan, S., Chen, J., Yin, Y., Li, L., Chen, J., Jiang, W., Cao, W., Kim, C., et al. (2025) · Science Advances · doi:10.1126/sciadv.adt4881 · Cited by 7
Quantifying cellular dynamics in mice using a novel fluorescent division reporter system
Lukas, E., Hogan, T. V., Williams, C., Seddon, B. P., & Yates, A. J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1157705 · Cited by 7
“The diversity of the naive T cell repertoire is supplemented by continued production of new T cells from the thymus (11), and any proliferative renewal of existing naive T cells acts to preserve it (16).”
BackgroundSex- and age-specific aspects of human peripheral T-cell dynamics
Mika, J., Yoshida, K., Kusunoki, Y., Candéias, S. M., & Polańska, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1224304 · Cited by 10
Durable CD4+ T cell immunity: cherchez la stem
Hughes, E. P., Syage, A. R., & Tantin, D. R. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.01.004 · Cited by 7
Pham, T.-N., Coupey, J., Rousseau, M., Thariat, J., & Valable, S. (2024) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiae156 · Cited by 7
Thymic microenvironment’s impact on immunosenescence
Li, L., Xu, F., Han, Y., Zeng, J., Du, S., & Wang, C. (2024) · Immunologic Research · doi:10.1007/s12026-024-09519-z · Cited by 8
van der Heiden, M., van Ravenhorst, M. B., Bogaard, M., Boots, A. M. H., Berbers, G. A. M., & Buisman, A. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.12.014 · Cited by 6
“Moreover, a shift in the T-cell compartment from more naïve to senescent memory T-cells with age, as well as increased numbers of regulatory T-cells [27-30], may have diminished the T-cell response towards the carrier protein in the middle-aged adults and subsequently have affected the humoral response, but this is cu…”
Molecular Heterogeneity in Large-Scale Biological Data: Techniques and Applications
Deng, C., Daley, T., Brandine, G. D. S., & Smith, A. D. (2019) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-072018-021339 · Cited by 8
Leaving no one behind: tracing every human thymocyte by single-cell RNA-sequencing
Deng, Y., Chen, H., Zeng, Y., Wang, K., Zhang, H., & Hu, H. (2021) · Seminars in Immunopathology · doi:10.1007/s00281-020-00834-9 · Cited by 7
T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation
Melsen, J. E., Dam, M. M. V. O.-T., van den Akker, E. B., Welters, M. J. P., Heezen, K. C., Pico‐Knijnenburg, I., Kolijn, P. M., Bredius, R. G. M., van Doorn, R., Langerak, A. W., et al. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01279-5 · Cited by 6
Zhao, C., Marrero, I., Narsale, A. A., Moya, R., & Davies, J. D. (2015) · Cellular Immunology · doi:10.1016/j.cellimm.2015.04.002 · Cited by 7
Single-Cell Resolution of T Cell Immune Responses
Buchholz, V. R., & Floßdorf, M. (2018) · Advances in immunology · doi:10.1016/bs.ai.2017.12.001 · Cited by 7
The Rules of Human T Cell Fate in vivo
del Amo, P. C., Debebe, J., Razavi-Mohseni, M., Nakaoka, S., Worth, A. T., Wallace, D. L., Beverley, P. C. L., Macallan, D. C., & Asquith, B. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00573 · Cited by 7
“memory and naïve T cells and the maintenance of naïve T cell homeostasis are very different in humans and mice (15).”
BackgroundGoggins, J. A., Kurtz, J. R., & McLachlan, J. B. (2020) · Pathogens · doi:10.3390/pathogens9080605 · Cited by 7
Extramedullary neutrophil progenitors: Quo Vadis?
Koenderman, L., & Vrisekoop, N. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01191-5 · Cited by 6
“In the adult mouse the main source of naïve T-cells in the periphery is the thymus, whereas in adult man the majority of naïve cells originates from peripheral proliferation [9].”
Self-citationAbnormal Immune Profile in Individuals with Kabuki Syndrome
Comel, M., Saad, N., Sil, D., Apparailly, F., Willems, M., Djouad, F., Andrau, J., Lozano, C., & Geneviève, D. (2024) · Journal of Clinical Immunology · doi:10.1007/s10875-024-01796-5 · Cited by 6
Long‐term immunological changes after corrective cardiac surgery
Eltan, S. B., Amirov, R., Babayeva, R., Altunbaş, M. Y., Karakurt, L. T., Can, S., Gungoren, E. Y., Bozkurt, S., Ozturk, N. K., Çatak, M. C., et al. (2024) · Scandinavian Journal of Immunology · doi:10.1111/sji.13418 · Cited by 6
Per-cell histone acetylation is associated with terminal differentiation in human T cells
Cheng, Y., Li, Y., Hu, Y., Li, Q., Li, Y., & Li, Y. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01634-w · Cited by 6
“For instance, replenishing the naïve T cell pool in mice largely relies on thymic output, whereas in humans maintenance of naïve T cells depends on renewal in the periphery [32].”
BackgroundNikitich, A., Helmlinger, G., Peskov, K. V., & Bocharov, G. A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1357706 · Cited by 6
“The estimated maximal rate of homeostatic T cell proliferation in the spleen was veri fi ed against data in mice which underwent thymectomy (30).”
BackgroundModeling the CD8＋ T cell immune response to influenza infection in adult and aged mice
Whipple, B., Miura, T. A., & Hernandez-Vargas, E. A. (2024) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2024.111898 · Cited by 7
Chen, L., Lin, A., Luo, P., & Miao, K. (2025) · Nano Research · doi:10.26599/nr.2025.94907609 · Cited by 6
Rane, S., Das, R., Ranganathan, V., Prabhu, S. B., Das, A., Mattoo, H., Durdik, J. M., George, A., Rath, S., & Bal, V. (2014) · BMC Biology · doi:10.1186/s12915-014-0106-0 · Cited by 6
“As thymic output decreases with age, naïve T cells in the periphery also appear to be longer-lived [16-18,31].”
BackgroundInfluentialZhou, Y. N., Leng, X., Mo, C., Zou, Q., Liu, Y., & Wang, Y. (2020) · Immunology Letters · doi:10.1016/j.imlet.2020.05.001 · Cited by 6
A discussion of immune tolerance and the layered immune system hypothesis
Mold, J. E., & Anderson, C. C. (2013) · Chimerism · doi:10.4161/chim.24914 · Cited by 6
Sprague, W. S., Troyer, R. M., Zheng, X., Wood, B. A., MacMillan, M., Carver, S., & VandeWoude, S. (2018) · Viruses · doi:10.3390/v10040210 · Cited by 6
“Peripheral naïve T cells were shown to be replenished by naïve thymic T cells in mice [22], and similar mechanisms may underlie our observations in this system.”
Homeostatic proliferation as a physiological process and a risk factor for autoimmune pathology
Shevyrev, D., Tereshchenko, V., Manova, O., & Va, K. (2020) · AIMS Allergy and Immunology · doi:10.3934/allergy.2021002 · Cited by 6
Interruption of Thymic Activity in Adult Mice Improves Responses to Tumor Immunotherapy
Almeida‐Santos, J., Bergman, M., Cabral, I. A., & Demengeot, J. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2000626 · Cited by 6
Metadata
- Authors
- den Braber, I., Mugwagwa, T., Vrisekoop, N., Westera, L., Mögling, R., Bregje de Boer, A., Willems, N., Schrijver, E. H. R., Spierenburg, G., Gaiser, K., Mul, E., Otto, S. A., Ruiter, A. F. C., Ackermans, M. T., Miedema, F., Borghans, J. A. M., de Boer, R. J., & Tesselaar, K.
- Affiliations
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Tesselaar, Kiki
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 36
- Issue
- 2
- Pages
- 288-297
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2069043306
- Cited by
- 572
- References
- 52
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 46 · 2023: 40 · 2022: 35 · 2021: 51 · 2020: 45 · 2019: 34 · 2018: 46 · 2017: 38 · 2016: 35 · 2015: 34 · 2014: 38 · 2013: 50 · 2012: 18
- FWCI
- 19.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 532 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Landsteiner Foundation for Blood Transfusion Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- naive T cells, T cell kinetics, T cell senescence, mouse-to-human extrapolation, thymectomy, TREC, CD31
- MeSH terms
- Adult, Aging, Animals, Child, Deuterium, Homeostasis, Humans, Infant, Newborn, Lymphopenia, Male, Mice, Inbred C57BL, Species Specificity, T-Lymphocytes, Thymus Gland, CD4-Positive T-Lymphocytes, Lymphocyte Count, Platelet Endothelial Cell Adhesion Molecule-1, Models, Animal, Cell Proliferation, Mice, Young Adult
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