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Peer-reviewedCC BYCell Reports

CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging

  • Kosuke Hashimoto1
  • Miki Kojima-Ishiyama2
  • Hajime Inokuchi3
  • Michihira Tagami2
  • Takashi Sasaki4
  • Kenji Mizuguchi5
  • Yasushi Okazaki2
  • Ichiro Taniuchi2
  • Kazuyoshi Ishigaki3
  • Nobuyoshi Hirose6
  • Piero Carninci7
  • Yasumichi Arai8
8 affiliations
  1. 1Institute for Protein Research, The University of Osaka, Osaka 565-0871, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. Electronic address: [email protected]
  2. 2RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
  3. 3RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-0016, Japan
  4. 4Centre for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-0016, Japan
  5. 5Institute for Protein Research, The University of Osaka, Osaka 565-0871, Japan
  6. 6Centre for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-0016, Japan. Electronic address: [email protected]
  7. 7RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Human Technopole, via Rita Levi Montalcini 1, Milan, Italy. Electronic address: [email protected]
  8. 8Centre for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-0016, Japan. Electronic address: [email protected]
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Abstract

Our previous study identified CD4 cytotoxic T lymphocytes (CD4 CTLs) as a hallmark of supercentenarians. CD4 CTLs have primarily been studied in disease contexts; however, their role in healthy aging remains unclear. Using single-cell immune profiling, we analyzed T cells from supercentenarians and found that CD4 CTLs begin to expand around the age of 100, characterized by sequential CD27/CD28 loss without exhaustion. CD4 CTLs were dominated by large clones, with top clones averaging 33.3%, indicating repeated stimulation by persistent antigens. Furthermore, CDR3β sequences of the top clones matched those of T cells expanded in tumors, particularly lung cancer. Ex vivo stimulation experiments revealed that CD4 CTLs consist of subgroups defined by interleukin expression patterns, suggesting their plasticity within the same clone. These findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through cancer suppression.

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Cite

BibTeXRIS
BibTeX
@article{hashimoto2026ctls,
  title = {{CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging}},
  author = {Kosuke Hashimoto and Miki Kojima-Ishiyama and Hajime Inokuchi and Michihira Tagami and Takashi Sasaki and Kenji Mizuguchi and Yasushi Okazaki and Ichiro Taniuchi and Kazuyoshi Ishigaki and Nobuyoshi Hirose and Piero Carninci and Yasumichi Arai},
  journal = {Cell Reports},
  year = {2026},
  month = aug,
  doi = {10.1016/j.celrep.2026.117728},
  url = {https://doi.org/10.1016/j.celrep.2026.117728},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging
AU  - Kosuke Hashimoto
AU  - Miki Kojima-Ishiyama
AU  - Hajime Inokuchi
AU  - Michihira Tagami
AU  - Takashi Sasaki
AU  - Kenji Mizuguchi
AU  - Yasushi Okazaki
AU  - Ichiro Taniuchi
AU  - Kazuyoshi Ishigaki
AU  - Nobuyoshi Hirose
AU  - Piero Carninci
AU  - Yasumichi Arai
PY  - 2026
DA  - 2026/08/19
JO  - Cell Reports
DO  - 10.1016/j.celrep.2026.117728
UR  - https://doi.org/10.1016/j.celrep.2026.117728
AB  - Our previous study identified CD4 cytotoxic T lymphocytes (CD4 CTLs) as a hallmark of supercentenarians. CD4 CTLs have primarily been studied in disease contexts; however, their role in healthy aging remains unclear. Using single-cell immune profiling, we analyzed T cells from supercentenarians and found that CD4 CTLs begin to expand around the age of 100, characterized by sequential CD27/CD28 loss without exhaustion. CD4 CTLs were dominated by large clones, with top clones averaging 33.3%, indicating repeated stimulation by persistent antigens. Furthermore, CDR3β sequences of the top clones matched those of T cells expanded in tumors, particularly lung cancer. Ex vivo stimulation experiments revealed that CD4 CTLs consist of subgroups defined by interleukin expression patterns, suggesting their plasticity within the same clone. These findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through cancer suppression.
SN  - 2211-1247
SN  - 2639-1856
ER  -