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Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- 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 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.<br />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.
- Subjects :
- Adult
CD4-Positive T-Lymphocytes
media_common.quotation_subject
Population
Biology
centenarian
Peripheral blood mononuclear cell
Clonal Evolution
Transcriptome
Interferon-gamma
Immunology and Inflammation
Immune system
Humans
Cytotoxic T cell
Receptor
education
Cells, Cultured
Aged
media_common
Aged, 80 and over
B-Lymphocytes
education.field_of_study
Multidisciplinary
Tumor Necrosis Factor-alpha
Gene Expression Profiling
T-cell receptor
aging
Longevity
Cell Differentiation
Middle Aged
Biological Sciences
single-cell transcriptome
CD4 CTL
PNAS Plus
Case-Control Studies
Immunology
Leukocytes, Mononuclear
Single-Cell Analysis
Ex vivo
CD8
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....0e53213bf0c25def7ac3b464f4cfe34e