Nuclear pore complex-mediated modulation of TCR signaling is required for naïve CD4(+) T cell homeostasis

Nuclear pore complexes (NPCs) are channels connecting the nucleus with the cytoplasm. We report that loss of the tissue-specific NPC component Nup210 causes a severe deficit of naïve CD4(+) T cells. Nup210-deficient CD4(+) T lymphocytes develop normally but fail to survive in the periphery. The decreased survival results from both an impaired ability to transmit tonic TCR signals and increased levels of Fas, which sensitize Nup210(−/−) naïve CD4(+) T cells to Fas-mediated cell death. Mechanistically, Nup210 regulates these processes by modulating the expression of Caveolin-2 (Cav2) and cJun at the nuclear periphery. While the TCR-dependent and CD4(+) T cell-specific upregulation of Cav2 is critical for proximal TCR signaling, cJun expression is required for STAT3-dependent repression of Fas. Our results uncover an unexpected role for Nup210 as a cell-intrinsic regulator of TCR signaling and T cell homeostasis; and expose NPCs as key players in the adaptive immune system.