Journal Article

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

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

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Adult / Age related diseases / Aged / Aged, 80 and over / Aging / B-Lymphocytes / Biological Sciences / Case-Control Studies / CD4 antigen / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - immunology / CD8 antigen / Cell Differentiation / Cells, Cultured / Centenarians / Clonal Evolution / Compression / Cytotoxicity / Gene expression / Gene Expression Profiling / Heterogeneity / Humans / Immune system / Immunology and Inflammation / Interferon-gamma - metabolism / Leukocytes (mononuclear) / Leukocytes, Mononuclear - physiology / Lymphocytes / Lymphocytes T / Middle Aged / Morbidity / Peripheral blood mononuclear cells / PNAS Plus / Single-Cell Analysis / T cell receptors / Toxicity / Transcription / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-α / γ-Interferon