A voltage-gated sodium channel is essential for the positive selection of CD4 ⁺ T cells

The sustained entry of Ca ²⁺ into CD4 ⁺ CD8 ⁺ double-positive thymocytes is required for positive selection. Here we identified a voltage-gated Na ⁺ channel (VGSC) that was essential for positive selection of CD4 ⁺ T cells. Pharmacological inhibition of VGSC activity inhibited the sustained Ca ²⁺ influx induced by positively selecting ligands and the in vitro positive selection of CD4 ⁺ but not CD8 ⁺ T cells. In vivo short hairpin RNA (shRNA)-mediated knockdown of the gene encoding a regulatory β-subunit of a VGSC specifically inhibited the positive selection of CD4 ⁺ T cells. Ectopic expression of VGSC in peripheral AND CD4 ⁺ T cells bestowed the ability to respond to a positively selecting ligand, which directly demonstrated that VGSC expression was responsible for the enhanced sensitivity. Thus, active VGSCs in thymocytes provide a mechanism by which a weak positive selection signal can induce the sustained Ca ²⁺ signals required for CD4 ⁺ T cell development.