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https://hdl.handle.net/10316/107233
Title: | Cell generation dynamics underlying naive T-cell homeostasis in adult humans | Authors: | Mold, Jeff E Réu, Pedro Olin, Axel Bernard, Samuel Michaëlsson, Jakob Rane, Sanket Yates, Andrew Khosravi, Azadeh Salehpour, Mehran Possnert, Göran Brodin, Petter Frisén, Jonas |
Issue Date: | Oct-2019 | Publisher: | Public Library of Science | Serial title, monograph or event: | PLoS Biology | Volume: | 17 | Issue: | 10 | 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. | URI: | https://hdl.handle.net/10316/107233 | ISSN: | 1545-7885 | DOI: | 10.1371/journal.pbio.3000383 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
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