Irradiation-Mediated Thymic Plasticity Is An Age-Related Phenomenon in Immunodeficient Mice.

Abstract 3677

Poster Board III-613

Successful T lymphopoiesis is essential for maintaining resistance to infection, mediating graft versus tumor activity, and as a platform for some immune based therapies. In mouse models of T cell immunodeficiency syndromes successful T cell reconstitution requires robust cellular reconstitution as well as remodeling of the thymic stroma. We have previously demonstrated that robust thymic lymphopoiesis in young IL-7 receptor deficient (IL7R−/−) mice can occur without prior irradiation and have linked this to the presence of intact stromal niches for DN3 precursors. In contrast to IL7R−/− mice, RAG−/− mice generate wild type T lymphocytes via thymic T lymphopoiesis after transfer of wild type precursors, but the thymus of transplanted RAG−/− mice remains hypocellular. As has been shown before, thymic cellularity of young RAG−/− mice can be rescued by irradiation followed by transfer of wild type precursors. We now demonstrate a profound difference between young and old RAG−/− mice in the thymic remodeling that occurs after irradiation and transfer of wild type hematopoietic stem cells. While the thymi of young RAG−/− mice undergo profound remodeling and develop normal cortico-medullary areas with segregation of single positive cells to the medulla, older RAG−/− mice do not undergo this remodeling and the cortical and medullary stroma remains less organized and more interdigitated. In addition, while the thymi of these older RAG−/− mice do develop small nests of medullary thymic epithelial cells (identified by flow cytometry and immunohistochemistry) not visualized in the untreated RAG−/− mice, these cells do not appropriately express MHC and these thymi do not appropriately segregate single positive developing T lymphocytes to these medullary areas. In vitro testing of sorted single positive thymocytes from these mice demonstrates failure of appropriate negative selection. Together these studies identify a specific defect in the thymic stroma of aging immunodeficient mice preventing appropriate de novo T lymphopoiesis.