Abstract
Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size.
Highlights
Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking
We focused on genes that govern pathways highly enriched at the earliest stages in TEC development, which included cell cycle, ribosomal biogenesis, and other genes downstream of Myc, with the presumption that these control the rapid expansion in thymic size observed in early life
We discovered increased expression of gene targets of Myc at fetal stages in development, including genes controlling ribosomal biogenesis and the cell cycle
Summary
Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; inducible expression of Myc in adult TEC promotes thymic growth. We determine genes underlying the transcriptional programs that differ between fetal and adult TEC, and identify Myc and downstream Myc target genes as controllers of the rapid expansion in thymus size from embryonic stages until young adulthood. Our results provide insight into mechanisms that underlie functional differences between fetal and adult TEC They establish that Myc activity in TEC restricts thymus size through life and provide a clear demonstration that Myc activity controls organ size in vertebrates
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