Inhibition of T cell proliferation by selective block of Ca 2+ -activated K + channels

Abstract

T lymphocytes express a plethora of distinct ion channels that participate in the control of calcium homeostasis and signal transduction. Potassium channels play a critical role in the modulation of T cell calcium signaling, and the significance of the voltage-dependent K channel, Kv1.3, is well established. The recent cloning of the Ca²⁺-activated, intermediate-conductance K⁺ channel (IK channel) has enabled a detailed investigation of the role of this highly Ca²⁺-sensitive K⁺ channel in the calcium signaling and subsequent regulation of T cell proliferation. The role IK channels play in T cell activation and proliferation has been investigated by using various blockers of IK channels. The Ca²⁺-activated K⁺ current in human T cells is shown by the whole-cell voltage-clamp technique to be highly sensitive to clotrimazole, charybdotoxin, and nitrendipine, but not to ketoconazole. Clotrimazole, nitrendipine, and charybdotoxin block T cell activation induced by signals that elicit a rise in intracellular Ca²⁺—e.g., phytohemagglutinin, Con A, and antigens such as Candida albicans and tetanus toxin in a dose-dependent manner. The release of IFN-γ from activated T cells is also inhibited after block of IK channels by clotrimazole. Clotrimazole and cyclosporin A act synergistically to inhibit T cell proliferation, which confirms that block of IK channels affects the process downstream from T cell receptor activation. We suggest that IK channels constitute another target for immune suppression.