Foxn1 and the Rise and Fall of the Thymic Microenvironment.

Abstract SCI-50

The postnatal thymus is the primary source of T cells in vertebrates, and many if not all stages of thymocyte development require interactions with thymic epithelial cells (TECs). There is abundant and growing evidence that the cellular and compartmental organization of the thymus is crucial for optimal organ function. Changes in the organization and stromal composition of the thymus as a result of genetic changes or during aging-associated involution can negatively impact both T cell production and function. The TEC-specific transcription factor Foxn1 is a critical regulator of these processes. I will present data from our Foxn1 allelic series showing that Foxn1 regulates TEC proliferation and differentiation at both fetal and adult stages, and that Foxn1-dependent TEC differentiation is required to assemble the multiple cell types that make up the complex structure of the functional thymus. Thus, Foxn1 is a central regulator throughout the life cycle of the thymus, and orchestrates both fetal organ formation and maintenance of the postnatal thymus. In vivo analysis of thymic function and stromal phenotypes is made difficult by the cellular complexity of the thymic microenvironment. I will also present data from a new quantitative, theoretical approach we are using to generate a “geographical map” of the cellular organization of the thymus. This approach will allow us to determine the spatial relationships of identifiable cell types, allowing us to generate new hypotheses about functional parameters of tissue organization at the cellular level. Thus, these results will provide a novel approach to generating quantitative and predictive models of the spatial and functional architecture of the thymic microenvironment.