Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians

Kosuke Hashimoto, Tsukasa Kouno, Tomokatsu Ikawa, Norihito Hayatsu, Yurina Miyajima, Haruka Yabukami, Tommy Terooatea, Takashi Sasaki, Takahiro Suzuki, Matthew Valentine, Giovanni Pascarella, Yasushi Okazaki, Harukazu Suzuki, Jay W. Shin, Aki Minoda, Ichiro Taniuchi, Hideyuki Okano, Yasumichi Arai, Nobuyoshi Hirose, Piero Carninci

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24242-24251
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number48
DOIs
Publication statusPublished - 2019 Nov 26

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Keywords

  • Aging
  • CD4 CTL
  • Centenarian
  • Single-cell transcriptome

ASJC Scopus subject areas

  • General

Cite this

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. (2019). Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proceedings of the National Academy of Sciences of the United States of America, 116(48), 24242-24251. https://doi.org/10.1073/pnas.1907883116