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Background: Voltage‐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. Methods: We 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. Results: We 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, Cav1.3 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 Cav1.3 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. Conclusions: Thus, Cav1.2 and Cav1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment. [ABSTRACT FROM AUTHOR]

Background: Type-17 inflammation characterizes psoriasis, a chronic skin disease. Because several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in T H 17 cells may be beneficial in psoriasis. We found that Ca v 1.4, encoded by CACNA1F, was the only Ca v 1 calcium channel expressed in T H 17 cells., Objective: We sought to investigate the role of Ca v 1.4 expression in early T H 17-activation events and effector functions, as well as its association with T H 17 signature genes in lesional psoriatic (LP) skins., Methods: Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Ca v 1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Ca v 1.4 in T H 17 activation and effector functions in a 3-dimensional skin reconstruction model., Results: CACNA1F expression correlated with inflammatory cytokine expression that characterizes LP skins and was preferentially associated with RORC expression in CD4 + and CD4 - cells from LP biopsies. Nicardipine, a Ca v 1 channel antagonist, markedly reduced inflammatory cytokine production by T H 17 cells from blood or LP skin. This was associated with decreased TCR-induced early calcium events at cell membrane and proximal signaling events. The knockdown of Ca v 1.4 in T H 17 cells impaired cytokine production. Finally, Ca v 1 inhibition reduced the expression of the keratinocyte genes characteristic of T H 17-mediated psoriasis inflammation in human skin equivalents., Conclusions: Ca v 1.4 channels promote T H 17-cell functions both at the periphery and in inflammatory psoriatic skin., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

It has previously been reported that in ex vivo planar explants prepared from Xenopus laevis embryos, the intracellular pH (pHi) increases in cells of the dorsal ectoderm from stage 10.5 to 11.5 (i.e. 11-12.5 hpf). It was proposed that such increases (potentially due to H+ being extruded, sequestered, or buffered in some manner), play a role in regulating neural induction. Here, we used an extracellular ion-selective electrode to non-invasively measure H+ fluxes at eight locations around the equatorial circumference of intact X. laevis embryos between stages 9-12 (˜7-13.25 hpf). We showed that at stages 9-11, there was a small H+ efflux recorded from all the measuring positions. At stage 12 there was a small, but significant, increase in the efflux of H+ from most locations, but the efflux from the dorsal side of the embryo was significantly greater than from the other positions. Embryos were also treated from stages 9-12 with bafilomycin A1, to block the activity of the ATP-driven H+ pump. By stage 22 (24 hpf), these embryos displayed retarded development, arresting before the end of gastrulation and therefore did not display the usual anterior and neural structures, which were observed in the solvent-control embryos. In addition, expression of the early neural gene, Zic3, was absent in treated embryos compared with the solvent controls. Together, our new in vivo data corroborated and extended the earlier explant-derived report describing changes in pHi that were suggested to play a role during neural induction in X. laevis embryos.

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., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)