Separation of the CaV1.2- CaV1.3 calcium channel duo prevents type 2 allergic airway inflammation

Abstract

BackgroundVoltage- gated calcium (Cav1) channels contribute to T- lymphocyte activation. Cav1.2 and Cav1.3 channels are expressed in Th2 cells but their respective roles are unknown, which is investigated herein.MethodsWe generated mice deleted for Cav1.2 in T cells or Cav1.3 and analyzed TCR- driven signaling. In this line, we developed original fast calcium imaging to measure early elementary calcium events (ECE). We also tested the impact of Cav1.2 or Cav1.3 deletion in models of type 2 airway inflammation. Finally, we checked whether the expression of both Cav1.2 and Cav1.3 in T cells from asthmatic children correlates with Th2- cytokine expression.ResultsWe demonstrated non- redundant and synergistic functions of Cav1.2 and Cav1.3 in Th2 cells. Indeed, the deficiency of only one channel in Th2 cells triggers TCR- driven hyporesponsiveness with weakened tyrosine phosphorylation profile, a strong decrease in initial ECE and subsequent reduction in the global calcium response. Moreover, Cav1.3Â has a particular role in calcium homeostasis. In accordance with the singular roles of Cav1.2 and Cav1.3 in Th2 cells, deficiency in either one of these channels was sufficient to inhibit cardinal features of type 2 airway inflammation. Furthermore, Cav1.2 and Cav1.3Â must be co- expressed within the same CD4+ T cell to trigger allergic airway inflammation. Accordingly with the concerted roles of Cav1.2 and Cav1.3, the expression of both channels by activated CD4+ T cells from asthmatic children was associated with increased Th2- cytokine transcription.ConclusionsThus, Cav1.2 and Cav1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment.Each of Cav1.2 and Cav1.3Â calcium channels plays a role in the full TCR- induced activation of Th2Â lymphocytes.Cav1.2 and Cav1.3 channels have concerted roles and must be co- expressed within the same CD4+ T cell to trigger allergic airway inflammation.Expression of both channels by CD4+ T cells from asthmatic children is associated with increased Th2- cytokine expression.Abbreviations: BM, bone marrow; Cav, voltage- gated calcium channel; i.n., intranasal; TCR, T cell receptor; Th, T helper cell; WT, wild- type