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

Mold, J. E. et al. (2019) Cell generation dynamics underlying naive T-cell homeostasis in adult humans. PLoS Biology, 17(10), e3000383. (doi: 10.1371/journal.pbio.3000383)

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.

• Item Type: Articles
• Additional Information: Funding: This work was supported by grants from the Swedish Research Council (https://www.vr.se/english.html; D0761801 to JF), Swedish Cancer Society (https://www.cancerfonden.se/om-cancerfonden/about-the-swedish-cancer-society; CAN 2016/505 to JF), Strategic Research Programme in Stem Cells and Regenerative Medicine (StratRegen) (https://ki.se/en/research/stratregen-research; to JF), Knut och Alice Wallenbergs Stiftelse (https://kaw.wallenberg.org; KAW 2018.0063), Torsten Söderbergs Stiftelse (professorship to JF), Portuguese Foundation for Science and Technology (https://www.fct.pt/fct.phtml.en; SFRH/BD/33465/2008 to PR), Human Frontiers Long-Term Fellowship (http://www.hfsp.org; LT-000231/2011-L to JEM), Swedish Society for Medicine (https://www.ssmf.se/about-ssmf-in-english/; SLS505921 to PB).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Yates, Professor Andrew
• Authors: Mold, J. E., Réu, P., Olin, A., Bernard, S., Michaëlsson, J., Rane, S., Yates, A., Khosravi, A., Salehpour, M., Possnert, G., Brodin, P., and Frisén, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS Biology
• Publisher: Public Library of Science
• ISSN: 1544-9173
• ISSN (Online): 1545-7885
• Copyright Holders: Copyright © 2019 Mold et al.
• First Published: First published in PLoS Biology 17(10):e3000383
• Publisher Policy: Reproduced under a Creative Commons license