Format

Send to

Choose Destination
PLoS Biol. 2019 Oct 29;17(10):e3000383. doi: 10.1371/journal.pbio.3000383. eCollection 2019 Oct.

Cell generation dynamics underlying naive T-cell homeostasis in adult humans.

Author information

1
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
2
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
3
Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
4
Institut Camille Jordan, CNRS UMR 5208, University of Lyon, Villeurbanne, France.
5
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
6
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
7
Institute of Infection, Immunity & Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.
8
Department of Physics and Astronomy, Ion Physics, Uppsala University, Uppsala, Sweden.
9
Department of Newborn Medicine, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31- naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center