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首页> 美国卫生研究院文献>The Journal of Experimental Medicine >The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation
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The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation

机译：与人CD1d分子结合的脂质的长度调节NKT细胞TCR的亲和力和NKT细胞活化的阈值

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CD1d-restricted lymphocytes recognize a broad lipid range. However, how CD1d-restricted lymphocytes translate T cell receptor (TCR) recognition of lipids with similar group heads into distinct biological responses remains unclear. Using a soluble invariant NKT (iNKT) TCR and a newly engineered antibody specific for α-galactosylceramide (α-GalCer)–human CD1d (hCD1d) complexes, we measured the affinity of binding of iNKT TCR to hCD1d molecules loaded with a panel of α-GalCer analogues and assessed the rate of dissociation of α-GalCer and α-GalCer analogues from hCD1d molecules. We extended this analysis by studying iNKT cell synapse formation and iNKT cell activation by the same panel of α-GalCer analogues. Our results indicate the unique role of the lipid chain occupying the hCD1d F′ channel in modulating TCR binding affinity to hCD1d–lipid complexes, the formation of stable immunological synapse, and cell activation. These data are consistent with previously described conformational changes between empty and loaded hCD1d molecules (Koch, M., V.S. Stronge, D. Shepherd, S.D. Gadola, B. Mathew, G. Ritter, A.R. Fersht, G.S. Besra, R.R. Schmidt, E.Y. Jones, and V. Cerundolo. 2005. Nat. Immunol 6:819–826), suggesting that incomplete occupation of the hCD1d F′ channel results in conformational differences at the TCR recognition surface. This indirect effect provides a general mechanism by which lipid-specific lymphocytes are capable of recognizing both the group head and the length of lipid antigens, ensuring greater specificity of antigen recognition.
机译：CD1d限制淋巴细胞识别广泛的脂质范围。然而，CD1d限制性淋巴细胞如何将具有相似组头的脂质的T细胞受体（TCR）识别转化为不同的生物学反应仍不清楚。使用可溶性不变NKT（iNKT）TCR和对α-半乳糖神经酰胺（α-GalCer）-人CD1d（hCD1d）复合物特异的新设计的抗体，我们测量了iNKT TCR与负载α的hCD1d分子结合的亲和力-GalCer类似物并评估了hCD1d分子中α-GalCer和α-GalCer类似物的解离速率。我们通过研究由同一组α-GalCer类似物组成的iNKT细胞突触形成和iNKT细胞激活来扩展此分析。我们的结果表明，占据hCD1d F'通道的脂质链在调节TCR与hCD1d-脂质复合物的结合亲和力，稳定的免疫突触形成和细胞活化中具有独特作用。这些数据与先前描述的空和加载的hCD1d分子之间的构象变化是一致的（Koch，M.，VS Stronge，D.Shepherd，SD Gadola，B.Mathew，G.Ritter，AR Fersht，GS Besra，RR Schmidt，EY Jones ，and V. Cerundolo。2005. Nat。Immunol 6：819-826），表明hCD1d F'通道的不完全占据导致TCR识别表面的构象差异。这种间接作用提供了一种通用机制，通过该机制脂质特异性淋巴细胞能够识别脂质抗原的组头和长度，从而确保更大的抗原识别特异性。

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