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

Nat Immunol. 2012 Sep;13(9):880-7. doi: 10.1038/ni.2379. Epub 2012 Jul 29.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • Flow Cytometry
  • Humans
  • Ion Channel Gating
  • Mice
  • Mice, Transgenic
  • NAV1.5 Voltage-Gated Sodium Channel
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium Channels / immunology*
  • Voltage-Gated Sodium Channel beta-4 Subunit


  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN4B protein, human
  • SCN5A protein, human
  • Scn5a protein, mouse
  • Sodium Channels
  • Voltage-Gated Sodium Channel beta-4 Subunit

Associated data

  • GEO/GSE38909