Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians
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Abstract
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
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Supercentenarians have lower levels of B cells, similar numbers of T cells, and a higher percentage of cytotoxic T cells in peripheral blood.
“Studies have shown lower levels of B cells, similar numbers of T cells, and a higher percentage of cytotoxic T cells in the peripheral blood of supercentenarians.318”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [318]
CD8+ cytotoxic T cells directly eradicate target cells using cytotoxic molecules via recognizing MHC I molecules within nearly all cells.
“CD8+ cytotoxic T cells directly eradicate target cells using cytotoxic molecules via recognizing MHC I molecules within nearly all cells [127].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [127]
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- Authors
- Hashimoto, K., Kouno, T., Ikawa, T., Hayatsu, N., Miyajima, Y., Yabukami, H., Terooatea, T., Sasaki, T., Suzuki, T., Valentine, M., Pascarella, G., Okazaki, Y., Suzuki, H., Shin, J. W., Minoda, A., Taniuchi, I., Okano, H., Arai, Y., Hirose, N., & Carninci, P.
- Affiliations
- RIKEN Center for Integrative Medical Sciences (JP)
- Keio University (JP)
- Corresponding author
- Hirose, Nobuyoshi
- Carninci, Piero
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-11-12
- Volume
- 116
- Issue
- 48
- Pages
- 24242-24251
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6883788
- OpenAlex
- W2983248500
- Cited by
- 343
- References
- 51
- Citations by year
- 2026: 45 · 2025: 49 · 2024: 56 · 2023: 59 · 2022: 51 · 2021: 52 · 2020: 28 · 2019: 3
- FWCI
- 13.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Keio University
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (17H04214, 19KK0222, 17H04090, 19H05747, 19H04820, 18K19569)
- RIKEN
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- supercentenarians, healthy aging, cytotoxic CD4+ T cells, clonal expansion, T cell receptor repertoire, peripheral blood mononuclear cells, immunosenescence, longevity, interferon-gamma, TNF-α
- MeSH terms
- Adult, Aged, Aged, 80 and over, B-Lymphocytes, Cell Differentiation, Cells, Cultured, Humans, Interferon-gamma, Leukocytes, Mononuclear, Middle Aged, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Case-Control Studies, Gene Expression Profiling, Single-Cell Analysis, Clonal Evolution
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