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 T cell receptor (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 Cav2(encoding Caveolin-2) and Junat the nuclear periphery. Whereas the TCR-dependent and CD4+T cell–specific upregulation of Cav2is 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. D’Angelo and colleagues show that the nucleoporin Nup210 plays a specific role in naïve CD4+T cell homeostasis by regulating expression of Caveolin-2, which is required for tonic TCR signaling.