Park Hyun Jung, Kim Tae-Cheol, Park Yun Hoo, Lee Sung Won, Jeon Jungmin, Park Se-Ho, Van Kaer Luc, Hong Seokmann
Department of Integrative Bioscience and Biotechnology, Institute of Anticancsoer Medicine Development, Sejong University, Seoul 05006, Korea.
Department of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea.
Biomedicines. 2021 Nov 4;9(11):1619. doi: 10.3390/biomedicines9111619.
We have previously shown that Vα14 TCR Tg (Vα14) 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 IFNγ and IL4 rapidly upon stimulation with α-galactosylceramide (α-GalCer), a prototypical iNKT cell agonist. However, the precise role of α-GalCer-activated iNKT cells in AD development remains unclear. Therefore, we examined whether repeated activation of iNKT cells with α-GalCer can regulate the pathogenesis of AD in Vα14 NC mice. We found that Vα14 NC mice injected repeatedly with α-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 Vα14 NC mice. Moreover, the severity of AD pathogenesis in α-GalCer-injected Vα14 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 α-GalCer-treated Vα14 NC mice. Collectively, our results have demonstrated the adverse effect of repeated α-GalCer treatment on skin inflammation mediated by type 2 immunity.
我们之前已经表明，Vα14 TCR转基因（Vα14）NC/Nga（NC）小鼠体内双阴性（DN）不变自然杀伤T（iNKT）细胞数量增加，这些细胞可预防特应性皮炎（AD）的自发发展。iNKT细胞在受到典型的iNKT细胞激动剂α-半乳糖神经酰胺（α-GalCer）刺激后，可通过快速产生多种细胞因子（如IFNγ和IL4）来调节免疫反应。然而，α-GalCer激活的iNKT细胞在AD发展中的具体作用仍不清楚。因此，我们研究了用α-GalCer反复激活iNKT细胞是否能调节Vα14 NC小鼠的AD发病机制。我们发现，与注射赋形剂的Vα14 NC小鼠相比，反复注射α-GalCer的Vα14 NC小鼠表现出加重的AD症状（如更高的临床评分、IgE过度产生以及脾脏肥大细胞和中性粒细胞数量增加）。此外，注射α-GalCer的Vα14 NC小鼠中AD发病机制的严重程度与Th2细胞增加但Th1和Foxp3调节性T（Treg）细胞减少相关。此外，Th1/Th2和Treg/Th2平衡的改变与α-GalCer处理的Vα14 NC小鼠中2型细胞因子偏向性的iNKT细胞的偏向性扩增密切相关。总的来说，我们的结果证明了反复α-GalCer处理对由2型免疫介导的皮肤炎症的不利影响。
