TSC/mTOR Signalling Controls Thymocyte Development and Proliferation/Differentiation of T Lymphocytes and Nerve Cells

This thesis is focused on the role of the Tuberous Sclerosis Complex (TSC)/mammalian Target of Rapamycin (mTOR) pathway in the proliferation, survival and differentiation of T cells and PC12 nerve cells. TSC and mTOR play important roles in these cellular processes in different cell models. We wondered which could be the contribution of these pathways in T cells and in particular in thymic development and in another cellular model of differentiation like the PC12 cells. In the first part of the thesis the results of the studies on the differentiation of mature T cells are presented. The involvement of mTORCl and mTORC2 was analysed in these processes by pharmacological inhibition with Rapamycin. The mTOR complexes were found to affect cytokines expression by influencing DNA methylation of their promoters. The role of the TSC pathway in thymic development was then evaluated. TSC1 was genetically inactivated early on during thymic development. It was possible to observe an increase in proliferation and cell death of TSC1 deleted cells. The increased proliferation was due to increased mTORCl signalling, while the increased cell death results from increased FoxO activity, a consequence of defective mTORC2/Akt signalling. The last part of the thesis focuses on the study of the TSC pathway in PC12 cells, a model of neuronal differentiation. The TSC complex plays a critical role in balancing the processes of proliferation and neurosecretory functions in these cells by its ability to affect the β-catenin and REST pathways. The signalling loop that connects these three central players can alternatively control these important processes