Coppieters Ken, Van Beneden Katrien, Jacques Peggy, Dewint Pieter, Vervloet Ann, Vander Cruyssen Bert, Van Calenbergh Serge, Chen Guangwu, Franck Richard W, Verbruggen Gust, Deforce Dieter, Matthys Patrick, Tsuji Moriya, Rottiers Pieter, Elewaut Dirk
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, Ghent, Belgium.
J Immunol. 2007 Aug 15;179(4):2300-9. doi: 10.4049/jimmunol.179.4.2300.
The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) has been shown to be a potent activator of invariant NKT (iNKT) cells, rapidly inducing large amounts of both Th1 and Th2 cytokines upon injection in mice. The C-glycoside analog of alpha-GalCer (alpha-C-GalCer), by contrast, results in an enhanced Th1-type response upon activation of iNKT cells. We administered a single dose of these Ags to DBA/1 mice during the early induction phase of collagen-induced arthritis and demonstrated therapeutic efficacy of alpha-GalCer when administered early rather than late during the disease. Surprisingly, the Th1-polarizing analog alpha-C-GalCer also conferred protection. Furthermore, a biphasic role of IFN-gamma in the effect of iNKT cell stimulation was observed. Whereas in vivo neutralization of IFN-gamma release induced by either alpha-GalCer or alpha-C-GalCer early during the course of disease resulted in partial improvement of clinical arthritis symptoms, blockade of IFN-gamma release later on resulted in a more rapid onset of arthritis. Although no phenotypic changes in conventional T cells, macrophages, or APCs could be detected, important functional differences in T cell cytokine production in serum were observed upon polyclonal T cell activation, 2 wk after onset of arthritis. Whereas alpha-GalCer-treated mice produced significantly higher amounts of IL-10 upon systemic anti-CD3 stimulation compared with PBS controls, T cells from alpha-C-GalCer-treated mice, by contrast, produced substantially lower levels of cytokines, suggesting the involvement of different protective mechanisms. In conclusion, these findings suggest long-term, ligand-specific, time-dependent, and partially IFN-gamma-dependent immunomodulatory effects of iNKT cells in collagen-induced arthritis.
糖鞘脂α-半乳糖神经酰胺（α-GalCer）已被证明是不变自然杀伤T（iNKT）细胞的有效激活剂，在注射到小鼠体内后能迅速诱导大量Th1和Th2细胞因子产生。相比之下，α-GalCer的C-糖苷类似物（α-C-GalCer）在激活iNKT细胞后会导致Th1型反应增强。我们在胶原诱导性关节炎的早期诱导阶段给DBA/1小鼠单次注射这些抗原，结果表明α-GalCer在疾病早期而非晚期给药具有治疗效果。令人惊讶的是，具有Th1极化作用的类似物α-C-GalCer也具有保护作用。此外，还观察到IFN-γ在iNKT细胞刺激效应中具有双相作用。在疾病过程早期，体内中和由α-GalCer或α-C-GalCer诱导释放的IFN-γ会导致临床关节炎症状部分改善，而在疾病后期阻断IFN-γ释放则会导致关节炎发病更快。尽管在传统T细胞、巨噬细胞或抗原呈递细胞（APC）中未检测到表型变化，但在关节炎发病2周后多克隆T细胞激活时，观察到血清中T细胞细胞因子产生存在重要功能差异。与PBS对照组相比，α-GalCer处理的小鼠在全身性抗CD3刺激下产生的IL-10量显著更高，而相比之下，α-C-GalCer处理的小鼠的T细胞产生的细胞因子水平则显著更低，这表明涉及不同的保护机制。总之，这些发现表明iNKT细胞在胶原诱导性关节炎中具有长期、配体特异性、时间依赖性和部分IFN-γ依赖性的免疫调节作用。
