Singh A K, Wilson M T, Hong S, Olivares-Villagómez D, Du C, Stanic A K, Joyce S, Sriram S, Koezuka Y, Van Kaer L
Department of Microbiology and Immunology, Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, TN 37232-0295, USA.
J Exp Med. 2001 Dec 17;194(12):1801-11. doi: 10.1084/jem.194.12.1801.
Experimental autoimmune encephalomyelitis (EAE) serves as a prototypic model for T cell-mediated autoimmunity. V(alpha)14 natural killer T (NKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the nonpolymorphic major histocompatibility complex (MHC) class I-like protein CD1d. Here, we show that activation of V(alpha)14 NKT cells by the glycosphingolipid alpha-galactosylceramide (alpha-GalCer) protects susceptible mice against EAE. beta-GalCer, which binds CD1d but is not recognized by NKT cells, failed to protect mice against EAE. Furthermore, alpha-GalCer was unable to protect CD1d knockout (KO) mice against EAE, indicating the requirement for an intact CD1d antigen presentation pathway. Protection of disease conferred by alpha-GalCer correlated with its ability to suppress myelin antigen-specific Th1 responses and/or to promote myelin antigen-specific Th2 cell responses. alpha-GalCer was unable to protect IL-4 KO and IL-10 KO mice against EAE, indicating a critical role for both of these cytokines. Because recognition of alpha-GalCer by NKT cells is phylogenetically conserved, our findings have identified NKT cells as novel target cells for treatment of inflammatory diseases of the central nervous system.
实验性自身免疫性脑脊髓炎(EAE)是T细胞介导的自身免疫的典型模型。V(α)14自然杀伤T(NKT)细胞是T淋巴细胞的一个亚群,可识别由非多态性主要组织相容性复合体(MHC)I类样蛋白CD1d呈递的糖脂抗原。在此,我们表明糖鞘脂α-半乳糖神经酰胺(α-GalCer)激活V(α)14 NKT细胞可保护易感小鼠免受EAE侵害。β-GalCer可与CD1d结合,但不被NKT细胞识别,无法保护小鼠免受EAE侵害。此外,α-GalCer无法保护CD1d基因敲除(KO)小鼠免受EAE侵害,这表明完整的CD1d抗原呈递途径是必需的。α-GalCer赋予的疾病保护作用与其抑制髓鞘抗原特异性Th1反应和/或促进髓鞘抗原特异性Th2细胞反应的能力相关。α-GalCer无法保护IL-4 KO和IL-10 KO小鼠免受EAE侵害,这表明这两种细胞因子都起着关键作用。由于NKT细胞对α-GalCer的识别在系统发育上是保守的,我们的研究结果已将NKT细胞确定为治疗中枢神经系统炎性疾病的新型靶细胞。