| T-cell development occurs in the thymus. A recent emphasis on the function of different thymic compartments during aging, i.e. the thymic epithelial space (TES) where thymopoiesis occurs and the thymic perivascular space (PVS), prompted us to ask several important questions. First, does the thymus continue to produce new T-cells during adult life? Second, are there phenotypic differences between lymphocytes in the thymic PVS and TES to suggest that these are distinct lymphocyte populations? Finally, where do PVS lymphocytes originate? Using a molecular assay, we showed that T-cell receptor gene rearrangement, a crucial process of thymocyte development, continues in adult life. We found unique phenotypes of T-cells and B-cells in the thymic perivascular space suggesting that these cells originate from the periphery. Understanding the factors that regulate lymphocyte trafficking to the PVS may lead to insights into the mechanisms of age-related thymic atrophy and control of thymic function after birth. During development, the thymocytes within thymic epithelial space undergo proliferation, DNA breakage and repair and apoptosis. Although some of the signals and proteins that regulate these processes are known, the roles of other highly expressed proteins are not clear. Early studies of the breast cancer susceptibility gene, BRCA2, showed that this gene is highly expressed in the thymus. BRCA2 has been hypothesized to be involved in proliferation, DNA repair, and cell cycle checkpoints. Since these processes occur at high levels during thymus development, we used the thymus as a model to study BRCA2 expression and function. We found that BRCA2 mRNA is upregulated in (CD4, CD8) double positive thymocytes that have high levels of proliferation, DNA repair associated with T-cell receptor gene rearrangement, and apoptosis. We found that BRCA2 expression increases in proliferating T-cells but is not required for DNA breakage and repair associated with T-cell receptor gene rearrangement. Furthermore, we found that BRCA2 regulates spontaneous and etoposide-induced apoptosis. Taken together, these studies provide new insights into thymic function throughout life and may also lead to an increased understanding of mechanisms leading to human breast cancers. |
