title: A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells.
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.
authors: Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Wan-Lin
authors: WL
authors: Lo
authors: David L
authors: DL
authors: Donermeyer
authors: Paul M
authors: PM
authors: Allen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000276:immunology*; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C477263:SCN4B protein, human; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit