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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.

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


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.

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