Ca_v1.4 calcium channels control cytokine production by human peripheral T_H17 cells and psoriatic skin-infiltrating T cells.

Abstract

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_H17 cells may be beneficial in psoriasis. We found that Ca_v1.4, encoded by CACNA1F, was the only Ca_v1 calcium channel expressed in T_H17 cells. We sought to investigate the role of Ca_v1.4 expression in early T_H17-activation events and effector functions, as well as its association with T_H17 signature genes in lesional psoriatic (LP) skins. Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Ca_v1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Ca_v1.4 in T_H17 activation and effector functions in a 3-dimensional skin reconstruction model. 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_v1 channel antagonist, markedly reduced inflammatory cytokine production by T_H17 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_v1.4 in T_H17 cells impaired cytokine production. Finally, Ca_v1 inhibition reduced the expression of the keratinocyte genes characteristic of T_H17-mediated psoriasis inflammation in human skin equivalents. Ca_v1.4 channels promote T_H17-cell functions both at the periphery and in inflammatory psoriatic skin.