4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation
4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation
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DOI：
10.4049/jimmunol.180.4.2062
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Kang, Chang-Yuil
中科院分区：
文献类型：
--
作者：
Kim, Dong-Hyeon;Chang, Woo-Sung;Kang, Chang-Yuil
多项研究表明，TNF 受体超家族的成员 4-1BB (CD137) 在包括活化 T 细胞在内的多种免疫细胞上表达。然而，4-1BB 在自然杀伤 T (NKT) 细胞上的表达和作用尚未得到充分表征。在这项研究中，结果表明 4-1BB 在初始 NKT 细胞上不表达，但通过 TCR 与 α-半乳糖神经酰胺 (α-GalCer) 结合而在活化的 NKT 细胞上快速诱导。此外，3113（一种激动性抗 4-1BB 单克隆抗体）提供的 4-1BB 信号传导可促进 NKT 细胞活化，从而增强 α-GalCer 驱动的 NKT 细胞的细胞因子产生。当通过鼻内施用 α-GalCer 评估 NKT 细胞驱动的气道免疫反应时，用 3113 和 α-GalCer 治疗的小鼠的气道高反应性 (AHR) 和肺部炎症明显比单独用 α-GalCer 治疗的小鼠更严重。这些恶化伴随着 IL-4、IL-13 和 IFN-γ 产生的上调。有趣的是，在使用 α-GalCer（加或不加 3H3）治疗的 IL-4R α 缺陷小鼠中，AHR 并未出现，但在 WN-gamma 缺陷小鼠中，AHR 加剧。我们的研究表明 NKT 细胞上的 4-1BB 作为共刺激分子发挥作用，并加剧 NKT 细胞介导的 AHR 的诱导，而 AHR 依赖于 IL-4R α 介导的途径。
Multiple studies have demonstrated that 4-1BB (CD137), a member of the TNF receptor superfamily, is expressed on several immune cells including activated T cells. However, the expression and the role of 4-1BB on natural killer T (NKT) cells have not been fully characterized. In this study, it was shown that 4-1BB was not expressed on naive NKT cells but was rapidly induced on activated NKT cells by TCR engagement with alpha-galactosylceramide (alpha-GalCer). Also, 4-1BB signaling provided by 3113, an agonistic anti-4-1BB mAb, promoted NKT cell activation resulting in enhanced cytokine production of NKT cells driven by alpha-GalCer. When NKT cell-driven airway immune responses were evaluated by intranasal administration of alpha-GalCer, airway hyperresponsiveness (AHR) and lung inflammation were significantly more aggravated in mice treated with 3113 and alpha-GalCer than in mice treated with alpha-GalCer alone. These aggravations were accompanied by up-regulation of IL-4, IL-13, and IFN-gamma production. Interestingly, AHR was not developed in IL-4R alpha-deficient mice treated with alpha-GalCer with or without 3H3 but was exacerbated in WN-gamma-deficient mice. Our study suggests that 4-1BB on NKT cells functions as a costimulatory molecule and exacerbates the induction of NKT cell-mediated AHR, which is dependent on the IL-4R alpha-mediated pathway.