RT Journal Article
SR Electronic
T1 Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 643528
DO 10.1101/643528
A1 Kosuke Hashimoto
A1 Tsukasa Kouno
A1 Tomokatsu Ikawa
A1 Norihito Hayatsu
A1 Yurina Miyajima
A1 Haruka Yabukami
A1 Tommy Terooatea
A1 Takashi Sasaki
A1 Takahiro Suzuki
A1 Matthew Valentine
A1 Giovanni Pascarella
A1 Yasushi Okazaki
A1 Harukazu Suzuki
A1 Jay W. Shin
A1 Aki Minoda
A1 Ichiro Taniuchi
A1 Hideyuki Okano
A1 Yasumichi Arai
A1 Nobuyoshi Hirose
A1 Piero Carninci
YR 2019
UL http://biorxiv.org/content/early/2019/05/20/643528.abstract
AB Supercentenarians, people who have reached 110 years 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 seven supercentenarians and five younger controls. We identified a marked increase of cytotoxic CD4 T-cells (CD4 CTLs) coupled with a substantial reduction of B-cells as a novel signature of supercentenarians. Furthermore, single-cell T-cell receptor sequencing of two 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. 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.Significance Exceptionally long-lived people such as supercentenarians tend to spend their entire lives in good health, implying that their immune system remains active to protect against infections and tumors. However, their immunological condition has been largely unexplored. We profiled thousands of circulating immune cells from supercentenarians at single-cell resolution, and identified a large number of CD4 T-cells that have cytotoxic features. This characteristic is very unique to supercentenarians, because generally CD4 T-cells have helper, but not cytotoxic, functions under physiological conditions. We further profiled their T-cell receptors, and revealed that the cytotoxic CD4 T-cells were accumulated through clonal expansion. The conversion of helper CD4 T-cells to a cytotoxic variety might be an adaptation to the late stage of aging.