Species-Specific Activity of Glycolipid Ligands for Invariant NKT Cells
Species-Specific Activity of Glycolipid Ligands for Invariant NKT Cells
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DOI：
10.1002/cbic.201200095
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发表时间：
2012-06-18
期刊：
影响因子：
3.2
通讯作者：
Stocker, Bridget L.
中科院分区：
文献类型：
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作者：
Dangerfield, Emma M.;Cheng, Janice M. H.;Stocker, Bridget L.
免疫调节糖脂-半乳糖神经酰胺（a- galcer）与CD1d结合，作为不变性CD1d限制性自然杀伤样T细胞（iNKT细胞）的配体显示出强大的活性。已经合成了a-GalCer的结构类似物，以确定CD1d呈现和iNKT细胞激活所需的成分，然而，迄今为止，植物鞘苷4-羟基对iNKT细胞激活的重要性一直存在争议。为了澄清这一点，我们合成了两种4-脱氧a-GalCer类似物（鞘氨酸和鞘氨酸），并研究了它们激活小鼠和人类iNKT细胞的能力。分析显示，类似物在刺激小鼠iNKT细胞方面具有与a-GalCer相当的活性，但在刺激人类iNKT细胞方面受到严重损害。在这里，我们确定了物种特异性糖脂活性是由于人类iNKT细胞上的t细胞受体缺乏对类似物的识别，而不是人类CD1d分子上类似物的不足。根据这些结果，我们建议为人类iNKT细胞活性而开发的糖脂应该含有植物鞘苷基。
The immunomodulatory glycolipid a-galactosylceramide (a-GalCer) binds to CD1d and exhibits potent activity as a ligand for invariant CD1d-restricted natural killer-like T cells (iNKT cells). Structural analogues of a-GalCer have been synthesised to determine which components are required for CD1d presentation and iNKT cell activation, however, to date the importance of the phytosphingosine 4-hydroxyl for iNKT cell activation has been disputed. To clarify this, we synthesised two 4-deoxy a-GalCer analogues (sphinganine and sphingosine) and investigated their ability to activate murine and human iNKT cells. Analysis revealed that the analogues possessed comparable activity to a-GalCer in stimulating murine iNKT cells, but were severely compromised in their ability to stimulate human iNKT cells. Here we determined that species-specific glycolipid activity was due to a lack of recognition of the analogues by the T-cell receptors on human iNKT cells rather than insufficient presentation of the analogues on human CD1d molecules. From these results we suggest that glycolipids developed for potent iNKT cell activity in humans should contain a phytosphingosine base.