Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age
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A diverse array of T cells is required for defense against pathogens. The naive CD4 T-cell repertoire reaches its peak diversity by early human adulthood and is maintained until older age. Surprisingly, around age 70, this diversity appears to plummet abruptly. A similar qualitative pattern holds for the CD4 T memory-cell population. We used mathematical models to explore different hypotheses for how such a loss of diversity might occur. The prevailing hypotheses suggest that the loss of diversity is due to a decline in emigration of cells from the thymus or a contraction in total number of cells. Our models reject these mechanisms because they yield only a gradual and minimal decline in the repertoire instead of the observed sudden and profound decrease later in life. We propose that an abrupt decline in the repertoire could be caused by the accumulation of mutations (defined here as any cell-intrinsic heritable event) that provide a short-term fitness advantage to a small number of T-cell clones (e.g., by an increased division rate or decreased death rate), with the person as a whole incurring the long-term cost of a decreased ability to fight infections.
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In silico simulation predicted severe repertoire contraction in some individuals under markedly uneven homeostatic proliferation, independent of thymic function.
“In silico simulation of T cell homeostasis with age predicted severe repertoire contraction to occur in some individuals, under conditions of markedly uneven homeostatic proliferation and irrespective of thymic function”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Johnson et al., 2012
Simulations had highly variable outcomes, suggesting a large stochastic component in failure to maintain a diverse repertoire.
“simulations had highly variable outcomes suggesting a large stochastic component in the failure to maintain a diverse repertoire.”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Johnson et al., 2012
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Chasing the chains by testing them twice
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Karaca, A., Güner, Ö. R., Günçıkan, M. N., Yılmaz, M., Karadağ, G. G., Sözmen, N. N., Sağdur, L., Kınık, K., & Yılmaz, F. M. (2026) · BMC Infectious Diseases · doi:10.1186/s12879-026-12842-5
- Authors
- Johnson, P. L. F., Yates, A. J., Goronzy, J. J., & Antia, R.
- Affiliations
- Emory University (US)
- Albert Einstein College of Medicine (US)
- VA Palo Alto Health Care System (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-12-10
- Volume
- 109
- Issue
- 52
- Pages
- 21432-21437
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3535632
- OpenAlex
- W2105527855
- Cited by
- 94
- References
- 51
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 7 · 2021: 12 · 2020: 6 · 2019: 11 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 8
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- National Institutes of Health (AI093870, AI057266, AI090019)
- National Institute of General Medical Sciences (U01GM070749)
- National Institute of Allergy and Infectious Diseases (R01AI049334, U19AI090019, U19AI057266, R01AI093870)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Physical Sciences › Engineering › Biomedical Engineering › Artificial Immune Systems Applications
- Keywords
- naive CD4+ T cells, T cell receptor diversity, thymic involution, thymic emigration, aging, immunosenescence, clonal expansion, somatic mutation accumulation, T cell memory, division rate, cell death rate
- MeSH terms
- Aged, Aged, 80 and over, Aging, Humans, Mutation, Thymus Gland, CD4-Positive T-Lymphocytes, Cellular Senescence, Models, Immunological
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