Protein kinase C–dependent activation of CaV1.2 channels selectively controls human TH2-lymphocyte functions

Background In addition to calcium release–activated calcium channel/ORAI calcium channels, the role of voltage-gated calcium (Ca v 1) channels in T-cell calcium signaling is emerging. Ca v 1 channels are formed by α1 (Ca V 1.1 to Ca V 1.4) and auxiliary subunits. We previously demonstrated that mouse T H 2 cells selectively overexpressed Ca V 1.2 and Ca V 1.3 channels. Knocking down these channels with Ca v 1 antisense (AS) oligonucleotides inhibited T H 2 functions and experimental asthma. Objective We investigated the expression profile and role of Ca v 1 channels in human T-cell subsets, with a focus on T H 2 cells. Methods We compared the profile of Ca V 1 channel subunit expression in T-cell subsets isolated ex vivo from the blood of healthy donors, as well as in vitro –polarized T-cell subsets, and tested the effect of the Ca v 1 inhibitors nicardipine and Ca v 1.2AS on their functions. Results Ca V 1.4 expression was detectable in CD4 + T cells, ex vivo T H 1 cells, and T H 17 cells, whereas Ca v 1.2 channels predominated in T H 2 cells only. T-cell activation resulted in Ca v 1.4 downregulation, whereas Ca v 1.2 expression was selectively maintained in polarized T H 2 cells and absent in T H 1 or T H 9 cells. Nicardipine and Ca V 1.2AS decreased Ca 2+ and cytokine responses in T H 2, but not T H 1, cells. Protein kinase C (PKC) α/β inhibition decreased Ca 2+ and cytokine responses, whereas both calcium and cytokine responses induced by PKC activation were inhibited by nicardipine or Ca v 1.2AS in T H 2 cells. Conclusion This study highlights the selective expression of Ca v 1.2 channels in human T H 2 cells and the role of PKC-dependent Ca v 1.2 channel activation in T H 2 cell function. Blocking PKC or Ca v 1.2 channel activation in T H 2 cells might represent new strategies to treat allergic diseases in human subjects.