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https://hdl.handle.net/10316/107233
Título: | Cell generation dynamics underlying naive T-cell homeostasis in adult humans | Autor: | 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 |
Data: | Out-2019 | Editora: | Public Library of Science | Projeto: | 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/omcancerfonden/ 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 So¨derbergs 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-inenglish/; SLS505921 to PB). | Título da revista, periódico, livro ou evento: | PLoS Biology | Volume: | 17 | Número: | 10 | Resumo: | 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 | Direitos: | openAccess |
Aparece nas coleções: | I&D CNC - Artigos em Revistas Internacionais |
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Ficheiro | Descrição | Tamanho | Formato | |
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Cell-generation-dynamics-underlying-naive-Tcell-homeostasis-in-adult-humansPLoS-Biology.pdf | 3.27 MB | Adobe PDF | Ver/Abrir |
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