A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner
A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner
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DOI：
10.4049/jimmunol.179.4.2300
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Elewaut, Dirk
中科院分区：
文献类型：
--
作者：
Coppieters, Ken;Van Beneden, Katrien;Elewaut, Dirk
鞘糖脂a-半乳糖神经酰胺（α - galcer）已被证明是一种有效的不变性NKT （iNKT）细胞激活剂，在小鼠体内注射后迅速诱导大量Th1和Th2细胞因子。相比之下，α - galcer的c -糖苷类似物（α - c - galcer）在iNKT细胞激活时导致th1型反应增强。我们在胶原诱导关节炎的早期阶段给DBA/1小鼠单剂量这些Ags，并在疾病早期而不是晚期给药时证明了α - galcer的治疗效果。令人惊讶的是，th1极化的模拟α - c - galcer也具有保护作用。此外，我们还观察到ifn - γ在iNKT细胞刺激作用中的双相作用。在疾病早期由α - galcer或α - c - galcer诱导的体内中和ifn - γ释放导致临床关节炎症状的部分改善，而随后阻断ifn - γ释放导致关节炎发作更快。尽管常规T细胞、巨噬细胞或apc未检测到表型变化，但在关节炎发病2周后，多克隆T细胞激活后，血清中T细胞细胞因子产生的重要功能差异被观察到。与PBS对照相比，α - c - galcer处理的小鼠在全身抗cd3刺激下产生了大量的IL-10，相比之下，α - c - galcer处理的小鼠的T细胞产生了大量的细胞因子，这表明参与了不同的保护机制。总之，这些发现表明iNKT细胞在胶原诱导关节炎中的长期、配体特异性、时间依赖性和部分ifn - γ依赖性免疫调节作用。
The glycosphingolipid a-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.