Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria, Australia.
Nat Immunol. 2011 Jul 31;12(9):827-33. doi: 10.1038/ni.2076.
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding these disparate antigens, the NKT cell TCRs docked onto CD1d similarly, achieving this by flattening the conformation of the β-linked ligands regardless of the size of the glycosyl head group. Unexpectedly, the antigenicity of iGb3 was attributable to its terminal sugar group making compensatory interactions with CD1d. Thus, the NKT cell TCR molds the β-linked self ligands to resemble the conformation of foreign α-linked ligands, which shows that induced-fit molecular mimicry can underpin the self-reactivity of NKT cell TCRs to β-linked antigens.
自然杀伤 T 细胞 (NKT 细胞) 最有效的外来抗原是α连接的糖脂，而 NKT 细胞的自身反应涉及对结构上不同的β连接糖脂抗原的较弱识别。在这里，我们提供了 NKT 细胞 T 细胞抗原受体 (TCR) 对单糖和三糖β连接激动剂 β-半乳糖神经酰胺 (β-GalCer) 和异硫代半乳糖神经酰胺 (iGb3) 分别产生自身反应的机制。在结合这些不同的抗原时，NKT 细胞 TCR 以相似的方式与 CD1d 结合，通过使 β 连接配体的构象变平来实现这一点，而不管糖基头部基团的大小如何。出乎意料的是，iGb3 的抗原性归因于其末端糖基与 CD1d 形成补偿性相互作用。因此，NKT 细胞 TCR 使 β 连接的自身配体变形，使其类似于外来的 α 连接配体的构象，这表明诱导契合分子模拟可以为 NKT 细胞 TCR 对 β 连接抗原的自身反应提供基础。
