Structural Evaluation of Potent NKT Cell Agonists: Implications for Design of Novel Stimulatory Ligands
Structural Evaluation of Potent NKT Cell Agonists: Implications for Design of Novel Stimulatory Ligands
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DOI：
10.1016/j.jmb.2009.08.061
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发表时间：
2009-11-20
影响因子：
5.6
通讯作者：
Wilson, Ian A.
中科院分区：
文献类型：
--
作者：
Schiefner, Andre;Fujio, Masakazu;Wilson, Ian A.
自然杀伤 T (N-KT) 细胞是 T 细胞的一个子集，可通过半不变 αβ T 细胞受体 (NKT TCR) 被 CD1d-糖脂复合物激活。激活后，NKT 细胞会分泌参与 T 辅助细胞反应的调节细胞因子。 α-半乳糖神经酰胺 (α-GalCer) 由 CD1d 呈递，是一种有效的 NKT 细胞激动剂。最近发现 α-GalCer 脂肪酸部分的苯环取代在引发调节性细胞因子方面具有优越性。四种新的小鼠 CD1d-脂质复合物（五种结构）、一种新的 PBS-25 复合物和具有内源配体的 CD1d 的晶体结构（分辨率为 1.6-1.9 埃）表明，α-GalCer 苯基类似物使 A' 袋具有较小的结构差异，而对于 NKT TCR 识别很重要的鞘氨醇和半乳糖部分几乎保持不变。观察到的细胞因子释放谱差异似乎与 CD1d-糖脂复合物的稳定性增加有关，而不是与 NKT TCR 的亲和力增加有关。此外，比较不同晶体空间群中的小鼠 CD1d-糖脂复合物揭示了相当大的构象变化，特别是在 F' 口袋上方，这是与 NKT TCR 相互作用的主要位点。我们建议对鞘氨醇部分进行修饰或降低 α-GalCer 灵活性的其他取代可以稳定 F'-口袋。这些化合物可能会增加 CD1d 对 NKT TCR 的亲和力，并进一步增强 α-GalCer 衍生物的刺激和调节特性。 (C) 2009 Elsevier Ltd. 保留所有权利。
Natural killer T (N-KT) cells are a subset of T cells that are activated by CD1d-glycolipid complexes through a semi-invariant alpha beta T cell receptor (NKT TCR). Upon activation, NKT cells secrete regulatory cytokines that are implicated in T helper cell responses. alpha-Galactosylceramide (alpha-GalCer) is a potent NKT cell agonist when presented by CD1d. Phenyl ring substitutions of the alpha-GalCer fatty acid moiety were recently found to be superior in eliciting regulatory cytokines. Crystal structures of four new mouse CD1d-lipid complexes (five structures), a new PBS-25 complex, and CD1d with an endogenous ligand, at 1.6-1.9 angstrom resolution, reveal that the alpha-GalCer phenyl analogues impart minor structural differences to the A'-pocket, while the sphingosine and galactose moieties, important for NKT TCR recognition, remain virtually unchanged. The observed differences in cytokine-release profiles appear to be associated with increased stability of the CD1d-glycolipid complexes rather than increased affinity for the NKT TCR. Furthermore, comparison of mouse CD1d-glycolipid complexes in different crystallographic space groups reveals considerable conformational variation, particularly above the F'-pocket, the primary site of interaction with the NKT TCR. We propose that modifications of the sphingosine moiety or other substitutions that decrease alpha-GalCer flexibility would stabilize the F'-pocket. Such compounds might then increase CD1d affinity for the NKT TCR and further enhance the stimulatory and regulatory properties of alpha-GalCer derivatives. (C) 2009 Elsevier Ltd. All rights reserved.