Manipulating thymic epithelial cells to modulate thymic selection and reactivity of T cells 4106

Abstract Description T cells are activated in response to foreign antigens, enabling them to successfully defend the organism. However, this reactivity becomes problematic in auto-immune diseases, where T cells recognize self-antigens as foreign, and in transplantation, where T cells trigger rejection by attacking donor cells. Immunosuppression is a common treatment but has limitations and side effects, highlighting the need for novel strategies to manage T cell reactivity. T cells develop in the thymus, where they undergo a selection process that ensures self-tolerance via interactions with thymic epithelial cells (TEC). We hypothesize that engrafting third party TEC into a recipient thymus will promote development of T cells that are tolerant of donor cells. We have established a model where we can engraft donor TEC into the thymi of MHC-II KO mice. MHC-II KO mice lack CD4 T cells, making engrafted TEC the only promoters of selection. The emergence of peripheral CD4 T cells in engrafted mice reveals that donor TEC can influence selection. Initial results of a mixed lymphocyte reaction demonstrated that these cells are functional and respond as a function of the selecting MHC. Currently, we are validating imaging techniques to understand donor TEC organization within the recipient thymus. Collectively, these findings suggest a novel way to manipulate T cell reactivity via TEC manipulation, defining the framework for interventions to alter T cell reactivity in transplantation and autoimmunity. Funding Sources Supported by DoD W81XWH2210976 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)