Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and.
Department of Neurology, University of Tubingen, Tubingen D-72076, Germany.
J Immunol. 2014 Aug 1;193(3):1035-46. doi: 10.4049/jimmunol.1302898. Epub 2014 Jun 27.
CD1d-restricted NKT cells can be divided into two groups: type I NKT cells use a semi-invariant TCR, whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the CNS tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. In this article, we have addressed the mechanism of regulation, as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of myelin proteolipid proteins 139-151/I-A(s)-tetramer(+) cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells (DCs) in the periphery, as well as CNS-resident microglia, are inactivated after sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover, tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not α-galactosylceramide, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune-regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Because CD1 molecules are nonpolymorphic, the sulfatide-mediated immune-regulatory pathway can be targeted for development of non-HLA-dependent therapeutic approaches to T cell-mediated autoimmune diseases.
CD1d 限制性 NKT 细胞可分为两组：I 型 NKT 细胞使用半不变的 TCR，而 II 型表达相对多样化的 TCR。II 型 NKT 细胞的一个主要亚群识别髓鞘衍生的硫酸脑苷脂，并且在实验性自身免疫性脑脊髓炎（EAE）期间选择性富集在中枢神经系统组织中。我们已经表明，通过硫酸脑苷脂激活硫酸脑苷脂反应性 II 型 NKT 细胞可防止 EAE 的诱导。在本文中，我们研究了调节机制，以及单一免疫显性形式的合成硫酸脑苷脂是否可以治疗 SJL/J 小鼠中的进行性慢性和复发性 EAE。我们已经表明，硫酸脑苷脂反应性 II 型 NKT 细胞的激活导致淋巴组织和中枢神经系统组织中髓鞘蛋白脂蛋白蛋白 139-151/I-A(s)-四聚体(+)细胞的频率和效应功能显著降低。此外，硫酸脑苷脂给药后外周的 I 型 NKT 细胞和树突状细胞（DC）以及中枢神经系统驻留的小胶质细胞被失活，并且缺乏 I 型 NKT 细胞的小鼠不能免受疾病侵害。此外，来自接受硫酸脑苷脂处理的动物的耐受的 DC 可以将保护作用转移到未成熟的小鼠中。用合成顺式二十四碳烯酰硫酸脑苷脂治疗 SJL/J 小鼠，但不是用α-半乳糖基神经酰胺治疗，可以逆转进行性慢性和复发性 EAE。我们的数据强调了一种新的免疫调节途径，涉及 NKT 亚群相互作用，导致 I 型 NKT 细胞、DC 和小胶质细胞失活，从而抑制自身免疫。因为 CD1 分子是非多态性的，所以硫酸脑苷脂介导的免疫调节途径可以作为针对 HLA 非依赖性治疗方法的发展的靶点，用于治疗 T 细胞介导的自身免疫性疾病。
