Separation of the Ca(V)1.2-Ca(V)1.3 calcium channel duo prevents type 2 allergic airway inflammation

Background 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. Methods 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. Results 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. Conclusions 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.