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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Murine naive T cells survive about 30 days and divide from homeostatic proliferation only every 1-2 years.
“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
Human T cell generation in adulthood depends on peripheral proliferation of naive T cells.
“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
The number of divisions appears lower than needed to generate 10,000 descendants; TREC frequencies are more consistent with clonal sizes around 100 cells.
“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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BackgroundPerales, M., Goldberg, J. D., Yuan, J. D., Koehne, G., Lechner, L., Papadopoulos, E. B., Young, J. W., Jakubowski, A. A., Zaidi, B., Gallardo, H. F., et al. (2012) · Blood · doi:10.1182/blood-2012-06-437236 · Cited by 207 · see citing works
“The ages of the other 2 patients with detectable TRECs were 43 years (14-205) and 54 years (14-204).”
BackgroundHuman autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation
Jones, J., Thompson, S. A. J., Loh, P., Davies, J. L., Tuohy, O., Curry, A. J., Azzopardi, L., Hill-Cawthorne, G. A., Fahey, M. T., Compston, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1313654110 · Cited by 206 · see citing works
“However, this method is inexact: CD4naive cells can proliferate without loss of CD31 (26), and most CD31CD4naive cells are derived from peripheral proliferation (27).”
MethodSepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity
Jensen, I. J., Sjaastad, F. V., Griffith, T. S., & Badovinac, V. P. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701618 · Cited by 204 · see citing works
Thymus and aging: morphological, radiological, and functional overview
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How many TCR clonotypes does a body maintain?
Lythe, G., Callard, R. E., Hoare, R. L., & Molina-París, C. (2016) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2015.10.016 · Cited by 175 · see citing works
“In our model, the thymus is a source of new T cell specificities, whereas division of T cells in the periphery can only contribute to the survival or expansion of existing clonotypes (den Braber et al., 2012).”
BackgroundMethodInfluentialAge-associated remodeling of T cell immunity and metabolism
Han, S., Georgiev, P., Ringel, A. E., Sharpe, A. H., & Haigis, M. C. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.005 · Cited by 193 · see citing works
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The Biology of Recent Thymic Emigrants
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“Researchers have suggested that thymic output contributes much less than does peripheral T cell homeostasis to the maintenance of the naive T cell pool in humans compared with mice (12).”
Mechanisms of Fetal T Cell Tolerance and Immune Regulation
Rackaityte, E., & Halkias, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00588 · Cited by 171 · see citing works
“Mice depend on a sustained thymic output of naïve T cells throughout their lifetime (13) and neonatal thymectomy results in severe impairment of immune responses to infection and autoimmunity (14–16).”
BackgroundLong-term maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites
Thome, J. J. C., Grinshpun, B., Kumar, B. V., Kubota, M., Ohmura, Y., Lerner, H., Sempowski, G. D., Shen, Y., & Farber, D. L. (2016) · Science Immunology · doi:10.1126/sciimmunol.aah6506 · Cited by 162 · see citing works
Reduced naïve <scp>CD</scp> 8 <sup>+</sup> <scp>T</scp> ‐cell priming efficacy in elderly adults
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Understanding Early-Life Adaptive Immunity to Guide Interventions for Pediatric Health
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“ontogeny differ substantially, especially regarding T cell development [(8, 9)”
BackgroundUnderstanding immunosenescence and its impact on vaccination of older adults
Allen, J. C., Toapanta, F. R., Chen, W. H., & Tennant, S. M. (2020) · Vaccine · doi:10.1016/j.vaccine.2020.11.002 · Cited by 157 · see citing works
“However, this decrease in naïve T lymphocytes is compensated by an increase in terminally differentiated memory T cells as pathogens are encountered with age [33, 34].”
BackgroundShaping Variation in the Human Immune System
Liston, A., Carr, E. J., & Linterman, M. A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.08.002 · Cited by 145 · see citing works
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Pathogenic features of CD4+CD28– T cells in immune disorders
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The Janus Head of T Cell Aging – Autoimmunity and Immunodeficiency
Goronzy, J. J., Li, G., Yang, Z., & Weyand, C. M. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00131 · Cited by 133 · see citing works
“Ongoing thymic activity is necessary to maintain a naïve T cell compartment in the mouse where the decline in thymic output is responsible for the eventual loss in naïve T cells (den Braber et al., 2012).”
BackgroundAging and influenza vaccine-induced immunity
Dugan, H. L., Henry, C., & Wilson, P. C. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2019.103998 · Cited by 133 · see citing works
The Gracefully Aging Immune System
Boraschi, D., Aguado, M. T., Dutel, C., Goronzy, J. J., Louis, J. A., Grubeck‐Loebenstein, B., Rappuoli, R., & Giudice, G. D. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005624 · Cited by 133 · see citing works
Aging disturbs the balance between effector and regulatory CD4+ T cells
van der Geest, K. S. M., Abdulahad, W. H., Tete, S. M., Lorencetti, P. G., Horst, G., Bos, N. A., Kroesen, B., Brouwer, E., & Boots, A. M. H. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.11.005 · Cited by 131 · see citing works
Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome
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Immunology of the ageing kidney
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“Similar to previous reports, older age was associated with fewer naïve CD4+ T cells (Additional file 1: Figure S2b) [28, 29].”
Physiology and pathology of T-cell aging
Minato, N., Hattori, M., & Hamazaki, Y. (2020) · International Immunology · doi:10.1093/intimm/dxaa006 · Cited by 121 · see citing works
The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging
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“In humans, both mature naïve T cells and—to a lesser extent—RTE-enriched CD45RA+CD31+ subset of CD4 T cells (30)—keep ability to proliferate on the periphery (31, 32).”
Chaudhry, M. S., Velardi, E., Malard, F., & van den Brink, M. R. M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601100 · Cited by 119 · see citing works
Naive T cells: The crux of cellular immune aging?
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TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity
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T‐cell Immunoglobulin and ITIM Domain Contributes to CD 8+ T‐cell Immunosenescence
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“It is worth noting that findings in animal models do not necessarily represent the phenomenon in humans (den Braber et al., 2012).”
BackgroundImmune function in Amazonian horticulturalists
Blackwell, A. D., Trumble, B. C., Suarez, I. M., Stieglitz, J., Beheim, B., Snodgrass, J. J., Kaplan, H. S., & Gurven, M. (2016) · Annals of Human Biology · doi:10.1080/03014460.2016.1189963 · Cited by 107 · see citing works
“Unlike in mice, the majority of peripheral T cells in humans are actually produced through proliferation of na€ıve cells, rather than through thymic output (den Braber et al., 2012).”
BackgroundLymphoid tissue structure and HIV-1 infection: life or death for T cells
Zeng, M., Haase, A. T., & Schacker, T. W. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.04.002 · Cited by 106 · see citing works
Short-Chain Fatty Acids Augment Differentiation and Function of Human Induced Regulatory T Cells
Hu, M., Alhamwe, B. A., Santner‐Nanan, B., Miethe, S., Harb, H., Renz, H. E., Potaczek, D. P., & Nanan, R. K. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105740 · Cited by 106 · see citing works
“Although the size and scope of the naïve CD4+ T cell pool tends to be maintained by both thymic output and peripheral homeostatic proliferation throughout adulthood [56,57], there is a progressive reduction of the thymus output with a resulting decline in the naïve T cell pool and expansion of the oligoclonal T cell p…”
BackgroundLymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover
Westera, L., van Hoeven, V., Drylewicz, J., Spierenburg, G., van Velzen, J. F., de Boer, R. J., Tesselaar, K., & Borghans, J. A. M. (2015) · Aging Cell · doi:10.1111/acel.12311 · Cited by 96 · see citing works
“…the parameters obtained by 2 H 2 O labeling and T-cell receptor excision circle (TREC) analysis in a mathematical model devised previously by den Braber et al. (2012), we also quantified to what extent thymic output declines during healthy aging, and whether and how this decline is compensated…”
InfluentialSelf-citationHSC Aging and Senescent Immune Remodeling
Denkinger, M. D., Leins, H., Schirmbeck, R., Florian, M. C., & Geiger, H. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.10.008 · Cited by 105 · see citing works
“could show that, in humans, the naïve T population is largely maintained via cell division of naïve T cells in the periphery upon aging [24].”
Neonatal thymectomy reveals differentiation and plasticity within human naive T cells
van den Broek, T., Delemarre, E. M., Janssen, W. J. M., Nievelstein, R. A. J., Broen, J. C., Tesselaar, K., Borghans, J. A. M., Nieuwenhuis, E. E. S., Prakken, B. J., Mokry, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84997 · Cited by 104 · see citing works
“As thymic export stops or diminishes, the maintaining peripheral T cell pool proliferates, replenishing the peripheral space and gradually acquiring an effector/memory phenotype, as also seen in lymphopenic conditions and aging (8, 9, 13, 30).”
BackgroundInfluentialSelf-citationAdvanced model systems and tools for basic and translational human immunology
Wagar, L. E., DiFazio, R. M., & Davis, M. M. (2018) · Genome Medicine · doi:10.1186/s13073-018-0584-8 · Cited by 102 · see citing works
Dysregulation of Systemic Immunity in Aging and Dementia
Lutshumba, J., Nikolajczyk, B. S., & Bachstetter, A. D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.652111 · Cited by 103 · see citing works
Large-Scale and Comprehensive Immune Profiling and Functional Analysis of Normal Human Aging
Whiting, C. C., Siebert, J., Newman, A. M., Du, H.-W., Alizadeh, A. A., Goronzy, J. J., Weyand, C. M., Krishnan, E., Fathman, C. G., & Maecker, H. T. (2015) · PLoS ONE · doi:10.1371/journal.pone.0133627 · Cited by 100 · see citing works
Lymphocyte generation and population homeostasis throughout life
Yanes, R. E., Gustafson, C. E., Weyand, C. M., & Goronzy, J. J. (2016) · Seminars in Hematology · doi:10.1053/j.seminhematol.2016.10.003 · Cited by 100 · see citing works
“Here, it is important to appreciate differences in T cell homeostasis between mice and humans [14].”
BackgroundChronic inflammation and aging: DNA damage tips the balance
Cavanagh, M. M., Weyand, C. M., & Goronzy, J. J. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.04.003 · Cited by 99 · see citing works
“This finding is, perhaps, unsurprising in light of a recent study which uses analysis of T cell receptor excision circles in humans, and deuterated water labeling and thymectomy experiments in mice to show that over 90% of naı̈ve T cells in humans are derived from peripheral proliferation rather than thymic generation…”
ResultImmune Senescence: Relative Contributions of Age and Cytomegalovirus Infection
Mekker, A., Tchang, V. S., Haeberli, L., Oxenius, A., Trkola, A., & Karrer, U. W. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002850 · Cited by 98 · see citing works
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“These results are consistent with experiments showing that thymic emigration plays a minor role relative to T-cell turnover for the maintenance of naive T cells (20).”
Interleukin-7 and Immunosenescence
Nguyen, V., Mendelsohn, A., & Larrick, J. W. (2017) · Journal of Immunology Research · doi:10.1155/2017/4807853 · Cited by 96 · see citing works
“The notion that low IL-7R expression levels are beneficial for reaching healthy old age corresponds with previous observations that patients suffering from autoimmune disease express increased levels of the IL-7 receptor/ligand complex genes [101, 102, 104] and that antagonizing IL-7 or the IL-7R may offer possible tr…”
BackgroundExtremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging
Soto‐Heredero, G., Heras, M. M. G. D. L., Escrig-Larena, J. I., & Mittelbrunn, M. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-064501 · Cited by 97 · see citing works
Aged murine hematopoietic stem cells drive aging-associated immune remodeling
Leins, H., Mulaw, M., Eiwen, K., Sakk, V., Liang, Y., Denkinger, M., Geiger, H., & Schirmbeck, R. (2018) · Blood · doi:10.1182/blood-2018-02-831065 · Cited by 95 · see citing works
Smithey, M. J., Li, G., Venturi, V., Davenport, M. P., & Nikolich‐Žugich, J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201867 · Cited by 93 · see citing works
“likely the primary mechanism for maintenance of a diverse memory T cell pool throughout life in humans, whereas thymic output is likely the primary mechanism in mice (55).”
BackgroundPaiva, R., Lino, A. C., Bergman, M., Caramalho, Í., Sousa, A. E., Zelenay, S., & Demengeot, J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221955110 · Cited by 91 · see citing works
“Human RTEs are enriched in the CD31 cell subset (33) that represents 50–80% of the naïve cells in peripheral blood of healthy donors (Fig.”
BackgroundAsymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system
Sinclair, C., Bains, I., Yates, A. J., & Seddon, B. P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1304859110 · Cited by 90 · see citing works
Aging, inflammaging and immunosenescence as risk factors of severe COVID-19
Tizazu, A. M., Mengist, H. M., & Demeke, G. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00309-5 · Cited by 91 · see citing works
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Revisiting Thymic Positive Selection and the Mature T Cell Repertoire for Antigen
Vrisekoop, N., Monteiro, J. P., Mandl, J. N., & Germain, R. N. (2014) · Immunity · doi:10.1016/j.immuni.2014.07.007 · Cited by 88 · see citing works
“…this competition occurs in vivo within secondary lymphoid organs is not understood but it may impact the TCR repertoire in ways that have not yet been explored, particularly in adult humans where thymic output contributes little to the maintenance of the naive T cell pool (den Braber et al., 2012).”
BackgroundSelf-citationThe role of cytokines in the pathogenesis and treatment of HIV infection
Catálfamo, M., Saout, C. L., & Lane, H. C. (2012) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2012.05.007 · Cited by 88 · see citing works
“These data are consistent with a recent report that, in humans, the maintenance of the naïve CD4 T cells pool is mainly mediated by expansion of peripheral naïve T cells, and also provides evidence of the important role of peripheral homeostasis in HIV infection [52, 53].”
ResultThe naive T-cell receptor repertoire has an extremely broad distribution of clone sizes
de Greef, P. C., Oakes, T., Gerritsen, B., Ismail, M., Heather, J., Hermsen, R., Chain, B., & de Boer, R. J. (2020) · eLife · doi:10.7554/elife.49900 · Cited by 88 · see citing works
T Cell Immunosenescence in Aging, Obesity, and Cardiovascular Disease
Shirakawa, K., & Sano, M. (2021) · Cells · doi:10.3390/cells10092435 · Cited by 87 · see citing works
“Since naïve T cells in the periphery are primarily maintained by homeostatic proliferation after thymic involution, there is no doubt that T cells are strongly affected by aging, unlike other immune cell types that depend on the production of hematopoietic stem cells (HSCs) [31,32].”
BackgroundLymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults
Sauce, D., Larsen, M., Fastenackels, S., Roux, A., Gorochov, G., Katlama, C., Sidi, D., Sibony-Prat, J., & Appay, V. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201235 · Cited by 82 · see citing works
Functional and Homeostatic Impact of Age-Related Changes in Lymph Node Stroma
Thompson, H. L., Smithey, M. J., Surh, C. D., & Nikolich‐Žugich, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00706 · Cited by 84 · see citing works
“Mechanistic understanding of the naïve T cell maintenance programs across aging and across species (47) will be exceptionally important to immune rejuvenation strategies.”
BackgroundBuilding a T cell compartment: how immune cell development shapes function
Davenport, M. P., Smith, N. L., & Rudd, B. D. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0332-3 · Cited by 83 · see citing works
Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells
Hu, B., Jadhav, R. R., Gustafson, C. E., Saux, S. L., Ye, Z., Li, X., Tian, L., Weyand, C. M., & Goronzy, J. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.585168 · Cited by 83 · see citing works
“Even in young adults, less than 20% of T cell generation derives from thymic production, which further dwindles to less than 1% in middle-aged individuals (1, 7, 8).”
BackgroundHost Resistance and Immune Aging
Bandaranayake, T., & Shaw, A. C. (2016) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2016.02.007 · Cited by 85 · see citing works
T cell senescence and cardiovascular diseases
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“More recent data modeling T cell subset numbers and TREC frequencies support the conclusion that the T cell kinetics in humans are fundamentally different and that results from mouse models cannot be easily extrapolated to humans (den Braber et al., 2012).”
BackgroundHuman T Cell Memory: A Dynamic View
Macallan, D. C., Borghans, J. A. M., & Asquith, B. (2017) · Vaccines · doi:10.3390/vaccines5010005 · Cited by 78 · see citing works
“This is a field where animal data have led the way, but we need to know how best to use such animal data to inform human immunology, not just in terms of inter-species translation [58], but also in terms of real-world versus laboratory-environment.”
BackgroundSelf-citation
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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