Cortical Thymic Epithelium: Defining Developmental Pathways and Specialization for Positive Selection

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T-cells are key players in cell-mediated immune protection of the body, providing a highly efficient defense against viral and bacterial infection. The thymus represents the primary organ supporting the continuous development of new T-cells throughout an individual?s lifetime. T-cells recognize bacteria and viruses through specialized receptors on the cell surface, termed T-cell receptors (TCR). Each T-cell produced bears a receptor of a single specificity. Continuous generation of T-cells occurs throughout life. This process ensures that T-cells exhausted in the periphery during immune responses are replaced and that enough T-cells of sufficient receptor diversity are present within the body to protect against the vast range of potential foreign invaders to the body. Importantly, TCRs are generated in a random manner through the random joining of multiple gene segments encoding the T-cell receptor. Such random receptor generation gives rise to a huge array of potential TCR receptor specificities. The downside of such random TCR generation is that numerous T-cells are generated bearing useless non-functioning receptors, whereas others may generate T-cells that may recognize the bodies? own tissues potentially causing autoimmune responses. In order to prevent development of either of these two cell types, interactions of developing T-cells with epithelial cells of the thymus delete useless and auto-reactive T cells and provide survival signals to self-tolerant T-cells capable of providing efficient immune protection. Thymic epithelial cells (TEC) therefore represent a key cell type involved in the education of developing T-cells, with the number of T-cells produced by the thymus being directly related to the number of TEC capable of providing survival signals supporting T-cell maturation. Importantly, the thymus undergoes a progressive reduction in size with an increase in age, a process termed thymus atrophy. Less thymic epithelial cells persist, leading to a reduced capacity to support T-cell development. This ultimately causes a reduced output of new T-cells. The potential functional results of which means that aged individuals gradually lose the range of T-cell diversity providing immune protection. In turn, this ultimately results in an increased susceptibility to infection with increasing age.It is therefore clear that the size of the thymus and numbers of thymic epithelial cells directly control the rate of T-cell production and therefore efficiency of immune protection. The mechanisms that regulate the expansion and development of thymic epithelial cells remain unclear. The primary focus of this research project is to accurately identify and isolate thymic epithelial progenitor cells and determine their capacity to generate mature, functional thymic tissue capable of supporting efficient T cell development. In addition, this study will also investigate the cellular-machinery that endows thymic epithelium with the highly specialized functional capacity to support the development of diverse, self-tolerant T-cells.