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

• Main Author: Mold, Jeff E
• Publication Date: 2019
• Other Authors: Réu, Pedro, Olin, Axel, Bernard, Samuel, Michaëlsson, Jakob, Rane, Sanket, Yates, Andrew, Khosravi, Azadeh, Salehpour, Mehran, Possnert, Göran, Brodin, Petter, Frisén, Jonas
• Format: Article
• Language: eng
• Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Download full: https://hdl.handle.net/10316/107233; https://doi.org/10.1371/journal.pbio.3000383
• topic: Adult; Aged; Aging; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Lineage; Cell Proliferation; Female; Gene Expression Regulation, Developmental; Homeostasis; Humans; Immunophenotyping; Interleukin-7; Lymphocyte Activation; Male; Middle Aged; NF-kappa B; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Signal Transduction; Thymus Gland

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.