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

Wan Lin Lo, David L. Donermeyer, Paul M. Allen

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)880-887
Number of pages8
JournalNature immunology
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2012

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