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. Rearrangement and expression of the T cell receptor (TCR) beta-chain marks commitment to the T cell lineage, which is followed by expression of the pre-TCR. Signals through the pre-TCR facilitate transition through the first checkpoint, known as beta-selection that selects for immature thymocytes expressing a functional TCR beta chain. We are interested in the molecular mechanisms involved in beta-selection. Recently, we have demonstrated that beta-catenin is a transcriptional target of pre-TCR signals and in turn regulates the expression of several proteins that are crucial for proper navigation of the beta-selection checkpoint. Thymocytes that successfully negotiate the beta-selection checkpoint rearrange and express the TCR alpha chain and the alpha-beta-TCR. The alpha-beta-TCR expressing thymocytes face a second checkpoint known as positive and negative selection where self-restricted but not self-reactive thymocytes are selected for further maturation. The molecular mechanisms that operate at this checkpoint are also of interest to our laboratory. We have shown that beta-catenin regulates positive selection of thymocytes. Positive selection and IL-7R signaling are both facilitated in mice expressing transgenic beta-catenin resulting in increased generation of CD8 T cells. Mature thymocytes migrate to the peripheral lymphoid organs such as the spleen and the lymph nodes where upon encountering antigen provide T cell mediated immune protection. Beta-catenin regulates mature T cell function by regulating cytokine production as well as proliferation in response to antigenic stimulation. Finally, transgenic mice expressing beta-catenin 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.
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