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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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“…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…”
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“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
“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 104
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 104
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
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 104
“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
“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. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002850 · Cited by 99
Johnson, P. L. F., Yates, A. J., Goronzy, J. J., & Antia, R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209283110 · Cited by 94
“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
“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 96
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
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
“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 98
“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 98
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 96
Zhang, H., Jadhav, R. R., Cao, W., Goronzy, I. N., Zhao, T. V., Jin, J., Ohtsuki, S., Hu, Z., Morales, J., Greenleaf, W. J., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01369-x · Cited by 86
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 96
“…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
“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 96
T Cell Immunosenescence in Aging, Obesity, and Cardiovascular Disease
Shirakawa, K., & Sano, M. (2021) · Cells · doi:10.3390/cells10092435 · Cited by 89
“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
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 87
“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 86
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 85
“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 88
T cell senescence and cardiovascular diseases
Yu, H. T., Park, S., Shin, E., & Lee, W. (2015) · Clinical and Experimental Medicine · doi:10.1007/s10238-015-0376-z · Cited by 84
Qi, Q., Zhang, D. W., Weyand, C. M., & Goronzy, J. J. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.005 · Cited by 80
“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 77
“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
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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