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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Robert, Virginie¹  Triffaux, Emily¹  Paulet, Pierre-Emmanuel¹  Guery, Jean-Charles¹  Pelletier, Lucette¹  Savignac, Magali¹ 

[1] Univ Toulouse 3, Ctr Physiopathol Toulouse Purpan, CNRS, INSERM,U1043,U5282, F-31062 Toulouse, France

关键词: Chemoattractant receptor-homologous molecule expressed on T(H)2 cells;    asthma;    calcium;    voltage-dependent calcium channels;    T(H)2 cytokines;    protein kinase C alpha/beta;   

DOI  :  10.1016/j.jaci.2013.10.038

来源: Elsevier

【 摘 要 】

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 alpha 1 (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 Ca2+ and cytokine responses in T(H)2, but not T(H)1, cells. Protein kinase C (PKC) alpha/beta inhibition decreased Ca2+ and cytokine responses, whereas both calcium and cytokine responses induced by PKC activation were inhibited by nicardipine or Cav1.2AS 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.

【 授权许可】

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