The thymus has great importance to human health as naïve T cells cannot be generated in its absence. The composition and organization of its specialized microenvironment are the foundation of the function of the thymus. In particular, thymic epithelial cells and the segregation of their subtypes, cortical thymic epithelial cells and medullary thymic epithelial cells, into distinct areas are required for positive and negative selection of developing thymocytes. However, these cells can be lost over time through natural age-related processes and through acute injury such as chemotherapy or radiation. The purpose of this thesis is to increase the understanding of how these losses can occur and to investigate therapies which may prevent or treat these losses. We first focus on a stem cell-based therapy for the improvement of thymopoiesis following radiation-based injury to the thymus. In it are discussed findings which describe different outcomes which may be achieved by selection of specific input populations. The disruption which the radiation-induced damage has on intrathymic migration of progenitors is also highlighted as well as the temporary nature of their stimulatory effects on thymic epithelial cells. Next, we also focus on thymic epithelial cell loss, but precipitated by advancing age. To facilitate these studies, a model of accelerated aging caused by deficiency in the gene klotho was used. We found that klotho deficiency did not impart an intrinsic defect in TEC longevity but that elements of the systemic aging environment were responsible for accelerated TEC loss in a TEC non-autonomous fashion. Specifically, high levels of vitamin D which accumulate in these mice were implicated in the induction of abnormal TEC apoptosis. Together the findings presented here advance the understanding of mechanisms which may be responsible for the loss of thymic epithelial cells, either age-related or clinically induced. Two strategies for the prevention or treatment of TEC loss are also discussed.
University of Minnesota Ph.D. dissertation.September 2016. Major: Microbiology, Immunology and Cancer Biology. Advisor: Bruce Blazar. 1 computer file (PDF); vi, 110 pages + 2 supplementary media files.
Mechanisms of Thymic Involution and Therapies to Prevent or Treat the loss of Thymic Epithelial Cells.
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