Revised Abstract Section Productive differentiation of thymic epithelium is critical for thymopoiesis and the establishment of self-tolerance. However, the differentiation program that forms the thymic environment is not well understood. Studies proposed here are intended provide the foundation to explore a model of TE differentiation that runs counter to the prevailing view, which has considered TE to be a fairly static population;one that is specified early during organogenesis to a thymic fate and one that requires the Foxn1 transcription factor to complete the post-specification program of TE differentiation. We are proposing that uncommitted TE progenitor cells persist in the postnatal thymus and that their progeny are continually being specified to a thymic fate through the action of Foxn1. According to this model, transient expression of Foxn1 defines a critical determining step in TE differentiation. We also propose that the maintenance of progenitor TE in the postnatal thymus is dependent on fibroblast growth factor signaling. Experiments proposed here will define Foxn1 as a marker of thymic epithelial heterogeneity and will generate molecular profiles of TE that we propose to represent discrete early stages of TE differentiation. In addition to the identification of candidate gene targets of Foxn1-regulation, this work will also provide the information required for the recovery of this population of thymic epithelial cells for functional studies in subsequent proposals. It is our hypothesis that regulation of this Foxn1+ thymic epithelial subset is centrally involved in the ill-defined process of age-related involution. Strategies to enhance the survival/expansion of these potential progenitor epithelial cells may lead to significantly enhanced thymic function in the elderly.
Thymic epithelial stem cells persist in the adult thymus, but their differentiation potential seems to decline with advancing age, leading to thymic involution. Understanding the program of thymic epithelial differentiation and the regulation of the program is necessary to reverse thymic involution and the loss of immune function that occurs in the elderly.
