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

Sustained Ca(2+) entry into CD4(+)CD8(+) double-positive thymocytes is required for positive selection. We identified a voltage-gated Na(+) channel (VGSC), essential for positive selection of CD4(+) T cells. Pharmacological inhibition of VGSC activity inhibitedsustained Ca(2+) influx induced by positive-selecting ligands and in vitro positive selection of CD4(+) but not CD8(+) T cells. In vivo shRNA knockdown of Scn5a specifically inhibited 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, directly demonstrating VGSC expression was responsible for increased sensitivity. Thus active VGSCs in thymocytes provide a mechanism by which a weak positive selecting signal can induce sustained Ca(2+) signals required for CD4(+) T cell development.