Authors:
Wan-Lin Lo, David L Donermeyer, & Paul M Allen
Summary:
The sustained entry of Ca2+ 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 Ca2+ 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 Ca2+ signals required for CD4+ T cell development.
Source:
Nature Immunology; 13, 880-887 (07/29/12)