Decline in the immune system is a feature of human aging. Reduction in naive T cell repertoire to combat novel pathogens stems from decreased function of the thymus where T cells develop. Stage-specific signal transduction and gene expression, resulting from reciprocal cell-cell interactions and locally produced cytokines and hormones, is critical for T cell development. Cues from stromal cells regulate an exquisite balance of proliferation, quiescence, cell-death and cell-fate decisions in developing thymocytes. In turn, thymocytes regulate the maturation of thymic epithelial cells. Understanding this interplay at a molecular level will provide insights that might be translated into novel therapies. We have found that transgenic mice expressing beta-catenin CAT-Tg mice exhibit accelerated age-dependent thymic involution and aging. The mechanistic basis for beta-catenin-mediated thymic involution remains a major focus of our laboratory. The long-term goal of our research is to delineate molecular interactions that significantly regulate T cell development in the thymus with the aim of further defining these processes and establish protocols to boost thymic function in the elderly and immunocompromised subjects. CAT-Tg mice also have increase in memory-like mature T cells. In particular, we are studying functional CAT-Tg CD8 memory T cells that protect mice from tumor formation to understand the role of beta-catenin-TCF1 in this process. We feel that insights gained from these studies have the potential to modulate the immune system to the advantage of elderly people and other people with inadequate immune systems.