Abstract
We have previously shown that Fibroblast growth factor 21 (Fgf21) is expressed in the thymus as well as in the liver. In line with this expression profile, Fgf21 was recently reported to protect against ageing-related thymic senescence by improving the function of thymic epithelial cells (TECs). However, the function of Fgf21 in the juvenile thymus remained to be elucidated. We investigated the physiological roles of Fgf21 in the juvenile thymus and found that young Fgf21 knockout mice, but not β-Klotho knockout mice nor adult Fgf21 knockout mice, showed a significant reduction in the percentage of single-positive CD4+ and CD8+ thymocytes without obvious alteration in TECs. Furthermore, treatment with recombinant FGF21 protein rescued the impairment in fetal thymus organ culture (FTOC) of Fgf21 knockout mice. Annexin V staining revealed FGF21 protein enhanced apoptosis of immature thymocytes undergoing selection process in FTOC, suggesting that FGF21 may facilitate the selection of developing T cells. Endocrine Fgf21 from the liver induced by metabolic stimulation did not affect juvenile thymocyte development. Our data suggest that Fgf21 acts as one of intrathymic cytokines in the neonatal and juvenile thymus, involving thymocyte development in a β-Klotho-independent manner.
Highlights
The fibroblast growth factor (Fgf) family consists of 22 human polypeptide growth factors that regulate various biological processes, including mitogenesis, cellular differentiation, and metabolism[1]
The thymus mainly consists of a large population of thymocytes and a small number of thymic epithelial cells (TECs), fibroblasts, and blood vessels, where thymocytes differentiate into mature T lymphocytes through the interaction with TECs
Since Kharitonenkov et al reported a biological function of FGF21 in improving lipid and carbohydrate homeostasis, and its potential therapeutic application for diabetes[2], the interest in FGF21 has focused on its functional analysis within metabolic tissues such as white and brown adipose tissue, as well as in that of the liver, pancreas, and hypothalamus[6]
Summary
The fibroblast growth factor (Fgf) family consists of 22 human polypeptide growth factors that regulate various biological processes, including mitogenesis, cellular differentiation, and metabolism[1]. Progenitor cells migrated from bone marrow lack the expression of CD4 and CD8 (termed as double negative cells: DN cells) These DN cells develop into both CD4 and CD8 positive cells (DP cells), followed by mature CD4 positive and CD8 negative cells (termed as CD4 single positive cells: CD4SP cells) or CD8 positive and CD4 negative cells (termed as CD8 single positive cells: CD8SP cells). The expression of Fgf[21] in the thymus suggests that Fgf[21] might play potential roles in thymic physiology In line with this prediction, Youm et al have recently shown that Fgf[21] protects thymic senescence by improving the function of TECs13. We investigated the physiological roles of Fgf[21] in thymic physiology in juveniles using Fgf[21] knockout mice and fetal thymus organ culture (FTOC)
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