Files
Abstract
The thymus is a primary lymphoid organ housing various stromal cells, such as thymic epithelial cells (TECs), that are vital for proper T-cell development (thymopoiesis), shaping adaptive immune systems in vertebrates. Positively correlating thymic size and naïve T-cell export change dynamically across the lifetime. The thymus exponentially increases its size and function from organogenesis to the perinatal stage; maintains homeostasis from the perinatal stage to adolescence; and starts to deteriorate after puberty. The molecular mechanisms behind each transition remain unidentified.Forkhead Box N1 (FOXN1) is a transcription factor required for thymic organogenesis, TEC differentiation, proliferation, and maintenance. Despite its TEC-restricted expression, FOXN1 also determines the maintenance of non-TEC stroma, such as mesenchyme and endothelium. As a lynchpin of thymus biology, FOXN1 is the focal point of this dissertation.
In this dissertation, we are going to explore how each transition occurs. In Chapter 1, we will show the down-regulation of insulin-like growth factor 2 (IGF2) is a likely suspect behind the thymic transition from neonatal expansion to juvenile homeostasis. Using time-series single- cell RNA sequencing, we report mesenchyme- and endothelium-derived IGF2 promotes proliferation in the neonatal murine thymus, causing rapid expansion. A premature decrease in Foxn1 gave rise to aged-like TECs and non-TEC stroma but did not affect the perinatal transition. In Chapter 2, we will show a premature decrease in Foxn1 is sufficient to cause an ageing-associated thymic atrophy, defined as thymic involution. We report an independent effect of thymic involution on thymopoiesis and ageing of peripheral T-cells. In Chapter 3, we will show a mis- and over-expression of Foxn1 is sufficient to reprogramme murine embryonic fibroblasts (MEFs) into TEC-like cells, capable of supporting thymopoiesis. With bulk- and single-cell RNA sequencing, we dissected the molecular mechanisms behind TEC differentiation.