Repeated alpha-GalCer Administration Induces a Type 2 Cytokine-Biased iNKT Cell Response and Exacerbates Atopic Skin Inflammation in V alpha 14(Tg) NC/Nga Mice

Abstract

We have previously shown that V alpha 14 TCR Tg (V alpha 14(Tg)) NC/Nga (NC) mice contain increased numbers of double-negative (DN) invariant natural killer T (iNKT) cells that protect against spontaneous development of atopic dermatitis (AD). iNKT cells can regulate immune responses by producing various cytokines such as IFN gamma and IL4 rapidly upon stimulation with alpha-galactosylceramide (alpha-GalCer), a prototypical iNKT cell agonist. However, the precise role of alpha-GalCer-activated iNKT cells in AD development remains unclear. Therefore, we examined whether repeated activation of iNKT cells with alpha-GalCer can regulate the pathogenesis of AD in V alpha 14(Tg) NC mice. We found that V alpha 14(Tg) NC mice injected repeatedly with alpha-GalCer display exacerbated AD symptoms (e.g., a higher clinical score, IgE hyperproduction, and increased numbers of splenic mast cells and neutrophils) compared with vehicle-injected V alpha 14(Tg) NC mice. Moreover, the severity of AD pathogenesis in alpha-GalCer-injected V alpha 14(Tg) NC mice correlated with increased Th2 cells but reduced Th1 and Foxp3(+) Treg cells. Furthermore, the resulting alterations in the Th1/Th2 and Treg/Th2 balance were strongly associated with a biased expansion of type 2 cytokine-deviated iNKT cells in alpha-GalCer-treated V alpha 14(Tg) NC mice. Collectively, our results have demonstrated the adverse effect of repeated alpha-GalCer treatment on skin inflammation mediated by type 2 immunity.