PROJECT SUMMARY Nuclear pore complexes (NPCs) are large multiprotein channels that connect the nucleus with the cytoplasm. In addition to their role in controlling nucleocytoplasmic transport, NPCs play key roles in gene expression regulation. The molecular mechanisms employed by NPCs and its components (nucleoporins) to regulate gene expression in mammalian cells are still poorly understood. Recent evidence indicates that NPCs have important functions in the immune system. CD4+ T lymphocytes are central players of the adaptive immune response. These cells assist B cells with antibody production, help CD8+ T lymphocytes to clear infections and to control tumor growth, stimulate macrophage activity, recruit immune cells to sites of active infection and inflammation, and exert regulatory roles that are essential to control the extent of the immune response. CD4+ T lymphocytes activate through the stimulation of their T cell receptor (TCR) at the plasma membrane. TCR engagement results in the initiation of the TCR signaling cascade that regulates T cell activation, proliferation, function and survival. We recently identified that the nuclear pore complex component Nup210 has a critical role in the transmission of TCR signals, and in the activation and survival of CD4+ T cells. We found that Nup210 regulates T cell activation by modulating gene expression in response to TCR stimulation. Our findings suggest that a coordinated activity between the plasma membrane and the nuclear envelope is required for the proper transmission of TCR signals and the efficient expression of TCR-induced genes. In this proposal we aim to establish how the TCR stimulation signal is communicated from the plasma membrane to Nup210 at NPCs (Aim 1), to dissect how Nup210 regulates the transcriptional activity NFAT and STAT transcription factors during TCR signaling (Aim 2), and to uncover the role of the Caveolin 2 protein in Nup210-regulation of TCR-induced gene expression (Aim 3). Besides offering novel insights into the mechanisms of gene expression modulation by nucleoporins, we expect our work will result in the characterization of a new mechanism of regulation of T cell function that could potentially be exploited to modulate T cell activity in immune-based therapies.