Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth

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.

Postnatal Involution and Counter-Involution of the Thymus

“…Defects in TEC development and numbers results in diminished thymic size (52). Moreover, dramatic expansion in TEC numbers in adulthood results in simultaneous expansion in the numbers of developing lymphocytes and severe thymic hyperplasia (51,(53)(54)(55). Correspondingly, and as mentioned previously, postnatal disruption of TECs triggers accelerated thymic atrophy (42,43).…”

“…We hope the enlarged thymus models discussed in this review will provide useful experimental tools to isolate greater numbers of adult cTECs to perform more detailed analysis of the changes that occur in this population with age. In addition, the newly refined genetic models described below will facilitate the ectopic expression of Myc specifically in cTEC or mTEC subsets (51). This could potentially determine whether such targeted manipulation is sufficient to reverse involution and force thymus growth.…”

Generation and Regeneration of Thymic Epithelial Cells

“…The shared expression of several markers e.g., CD205, Ly51, β5t, between cTEC and bipotent TEC progenitors makes the respective populations difficult to distinguish. However recent data from embryonic and adult TEC suggests differences now exist, and RNA sequencing analysis shows that embryonic TEC are enriched for genes involved in cell cycling and have a downregulation of genes involved in antigen presentation (9,26). Such studies may support future approaches to identify differentially expressed genes that help to define and isolate TEC and TEC progenitor subsets.…”

“…The presence of such epithelial-thymocyte complexes results in an estimated 20% of RNA isolated from total cTECs reflecting gene expression by enclosed DP thymocytes (24). This can be seen in single cell RNA sequencing of cTECs where newborn and adult cTECs appear to be contaminated with DP thymocytes (26). Recent single cell RNA sequencing analysis has begun to describe some heterogeneity within cTEC beyond TNC.…”

“…This important process limits the extent to which the thymus can grow, and therefore may contribute to agerelated thymus involution. Cowan et al (26) induced transgenic expression of Myc by TEC, which maintained a fetal gene signature in adult TEC, and caused excessive TEC proliferation and thymus hyperplasia in adult mice, suggesting this could be a mechanism by which to reverse age related thymic atrophy.…”