Separation of the Ca_V 1.2-Ca_V 1.3 calcium channel duo prevents type 2 allergic airway inflammation.

Abstract

Voltage-gated calcium (Ca_v 1) channels contribute to T-lymphocyte activation. Ca_v 1.2 and Ca_v 1.3 channels are expressed in Th2 cells but their respective roles are unknown, which is investigated herein. We generated mice deleted for Ca_v 1.2 in T cells or Ca_v 1.3 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 Ca_v 1.2 or Ca_v 1.3 deletion in models of type 2 airway inflammation. Finally, we checked whether the expression of both Ca_v 1.2 and Ca_v 1.3 in T cells from asthmatic children correlates with Th2-cytokine expression. We demonstrated non-redundant and synergistic functions of Ca_v 1.2 and Ca_v 1.3 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, Ca_v 1.3 has a particular role in calcium homeostasis. In accordance with the singular roles of Ca_v 1.2 and Ca_v 1.3 in Th2 cells, deficiency in either one of these channels was sufficient to inhibit cardinal features of type 2 airway inflammation. Furthermore, Ca_v 1.2 and Ca_v 1.3 must be co-expressed within the same CD4⁺ T cell to trigger allergic airway inflammation. Accordingly with the concerted roles of Ca_v 1.2 and Ca_v 1.3, the expression of both channels by activated CD4⁺ T cells from asthmatic children was associated with increased Th2-cytokine transcription. Thus, Ca_v 1.2 and Ca_v 1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment.