Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.
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.
持续的 Ca(2+)进入 CD4(+)CD8(+)双阳性胸腺细胞是阳性选择所必需的。在这里，我们鉴定了一种电压门控 Na(+)通道（VGSC），它对 CD4(+)T 细胞的阳性选择是必不可少的。VGSC 活性的药理学抑制抑制了由阳性选择配体诱导的持续 Ca(2+)内流和体外 CD4(+)但不是 CD8(+)T 细胞的阳性选择。体内短发夹 RNA（shRNA）介导的编码 VGSC 调节β亚基的基因敲低特异性抑制 CD4(+)T 细胞的阳性选择。VGSC 在周围 AND CD4(+)T 细胞中的异位表达赋予了对阳性选择配体的反应能力，这直接证明了 VGSC 表达负责增强敏感性。因此，胸腺细胞中的活性 VGSC 提供了一种机制，通过该机制，弱阳性选择信号可以诱导 CD4(+)T 细胞发育所需的持续 Ca(2+)信号。
