Activation-induced NKT cell hyporesponsiveness protects from α-galactosylceramide hepatitis and is independent of active transregulatory factors
Activation-induced NKT cell hyporesponsiveness protects from α-galactosylceramide hepatitis and is independent of active transregulatory factors
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DOI：
10.1189/jlb.0607352
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发表时间：
2008-07-01
影响因子：
5.5
通讯作者：
Tiegs, Gisa
中科院分区：
文献类型：
--
作者：
Biburger, Markus;Tiegs, Gisa
NK T（NKT）细胞是表达NK和T淋巴细胞特征的独特淋巴细胞，可以用糖脂抗原α-半乳糖基神经酰胺（α- GalCer）特异性活化。在人类和小鼠中，这种激活引起明显的细胞因子反应。在C57 BL/ 6小鼠中，α-GalCer注射另外诱导NKT介导的肝损伤，代表人类免疫介导的肝炎的模型。然而，小鼠的单次α-GalCer预处理防止了NKT介导的肝损伤、细胞因子应答（全身性地和局部地在肝脏中）以及在α- GalCer再激发时肝细胞Fas的上调。由于α-GalCer在临床试验中用作NKT细胞活化剂，因此耐受性诱导的研究显得至关重要。我们证明了α- GalCer耐受性不依赖于枯否细胞、IL- 10、胱天蛋白酶-3介导的凋亡或CD 4 CD 25 T调节细胞（T细胞），这些在其他免疫耐受性模型中是至关重要的。修正相关的，早期的方法，我们共培养高度纯化，非耐受和耐受肝NKT细胞离体，可以令人信服地排除相关的反式显性NKT T细胞。这些结果强烈表明α-GalCer诱导的耐受性仅由NKT细胞内在低反应性引起。耐受小鼠表现出肝内CD 4 NKT细胞亚群的特异性减少，而CD 4-细胞群基本上不受影响，并揭示了肝NKT细胞上α- GalCer特异性TCR和NKT共刺激物糖皮质激素诱导的TNFR相关蛋白的下调，而抑制性Ly 49 I增加.总之，α-GalCer耐受性可以作为肿瘤患者中经常观察到的NKT细胞低反应性的模型，并可能有助于开发其重新激活的策略。相反，使NKT细胞低反应的方法可能构成疾病的新治疗策略，其中异常NKT细胞活化是因果关系。
NK T ( NKT) cells, unique lymphocytes expressing features of NK and T lymphocytes, can specifically be activated with the glycolipid antigen alpha- galactosylceramide ( alpha- GalCer). In humans and mice, this activation provokes pronounced cytokine responses. In C57BL/ 6 mice, alpha-GalCer injection additionally induces NKT- mediated liver injury, representing a model for immune- mediated hepatitis in humans. However, a single alpha-GalCer pretreatment of mice prevented NKT- mediated liver injury, cytokine responses ( systemically and locally in the liver), and up- regulation of hepatocellular Fas upon alpha- GalCer rechallenge. As alpha-GalCer is used as a NKT cell- activating agent in clinical trials, an investigation of tolerance induction appears crucial. We demonstrate that alpha- GalCer tolerance does not depend on Kupffer cells, IL- 10, Caspase- 3- mediated apoptosis, or CD4 CD25 T regulatory cells ( Tregs), which are crucial in other models of immunological tolerance. Amending relevant, earlier approaches of others, we cocultivated highly purified, nontolerized and tolerized liver NKT cells ex vivo and could convincingly exclude the relevance of transdominant NKT Tregs. These results strongly suggest alpha-GalCer- induced tolerance to be exclusively caused by NKT cell intrinsic hyporesponsiveness. Tolerized mice showed specific diminishment of the intrahepatic CD4 NKT cell subpopulation, with the CD4 - population largely unaffected, and revealed downmodulation of alpha- GalCer- specific TCR and the NKT costimulator glucocorticoid- induced TNFR- related protein on liver NKT cells, whereas inhibitory Ly49I was increased. In conclusion, alpha-GalCer tolerance could serve as a model for the frequently observed NKT cell hyporesponsiveness in tumor patients and might help to develop strategies for their reactivation. Conversely, approaches to render NKT cells hyporesponsive may constitute new therapeutic strategies for diseases, where aberrant NKT cell activation is causally involved.