Unique interplay between sugar and lipid in determining the antigenic potency of bacterial antigens for NKT cells.
Unique interplay between sugar and lipid in determining the antigenic potency of bacterial antigens for NKT cells.
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DOI：
10.1371/journal.pbio.1001189
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发表时间：
2011-11
期刊：
影响因子：
9.8
通讯作者：
Zajonc DM
中科院分区：
文献类型：
--
作者：
Girardi E;Yu ED;Li Y;Tarumoto N;Pei B;Wang J;Illarionov P;Kinjo Y;Kronenberg M;Zajonc DM
结构和生物物理学研究揭示了诱导适应机制的基础上严格的特异性不变的自然杀伤T细胞的独特糖脂抗原的病原体肺炎链球菌。不变的自然杀伤T（iNKT）细胞是一种进化保守的T细胞群体，其特征在于先天性和适应性免疫应答的特征。研究表明，iNKT细胞是对革兰氏阳性病原体（如肺炎链球菌）的保护性应答所必需的，并且这些细胞识别由CD 1d（一种非经典抗原呈递分子）呈递的细菌二酰甘油抗原。这些抗原刺激iNKT细胞需要含有不寻常脂肪酸、异油酸以及葡萄糖的脂质骨架的组合，当与其他脂质连接时，葡萄糖较弱或不具有刺激性。在这里，我们进行了结构和生物物理研究，阐明了这种独特组合的严格要求的原因。数据表明，与CD 1d沟结合的异辛酸使突出的葡萄糖定向以识别TCR，并且当与TCR复合时，它允许葡萄糖与CD 1d形成额外的氢键。此外，TCR结合导致糖和CD 1d两者的诱导拟合，并且我们已经鉴定了对iNKT TCR识别和三元复合物的稳定性重要的CD 1d氨基酸。这些研究还显示了葡萄糖形成的氢键如何解释TCR与这种CD 1d-糖脂复合物的独特结合动力学。因此，我们的研究阐明了糖脂识别重要病原体抗原的机制。不变的自然杀伤T（iNKT）细胞是识别脂质抗原的进化上保守的免疫细胞群体。这些iNKT细胞表面上的一种称为T细胞抗原受体（TCR）的蛋白质识别与抗原呈递细胞表面上称为CD 1d的蛋白质结合的脂质。在这里，我们描述了CD 1d和iNKT TCR之间形成的复合物的三维结构，以及来自感染性细菌肺炎链球菌的糖脂抗原，这是成人细菌性脑膜炎的常见原因，也是许多其他肺炎球菌感染的原因。我们通过X射线晶体学确定了配合物的三维结构。获得的数据使我们能够理解使这种糖脂成为iNKT细胞的有效抗原的结构要求，以及为什么这些细胞的TCR识别己糖和二酰基甘油脂质的特定组合。此外，通过突变CD 1d和使用生物物理方法研究突变的蛋白质复合物，我们分析了CD 1d和TCR之间的蛋白质-蛋白质界面的作用，发现它在含有糖脂抗原的三分子复合物的稳定性中起重要作用，而不是形成。
Structural and biophysical studies reveal the induced-fit mechanism underlying the stringent specificity of invariant natural killer T cells for unique glycolipid antigens from the pathogen Streptococcus pneumoniae. Invariant natural killer T (iNKT) cells are an evolutionary conserved T cell population characterized by features of both the innate and adaptive immune response. Studies have shown that iNKT cells are required for protective responses to Gram-positive pathogens such as Streptococcus pneumoniae, and that these cells recognize bacterial diacylglycerol antigens presented by CD1d, a non-classical antigen-presenting molecule. The combination of a lipid backbone containing an unusual fatty acid, vaccenic acid, as well as a glucose sugar that is weaker or not stimulatory when linked to other lipids, is required for iNKT cell stimulation by these antigens. Here we have carried out structural and biophysical studies that illuminate the reasons for the stringent requirement for this unique combination. The data indicate that vaccenic acid bound to the CD1d groove orients the protruding glucose sugar for TCR recognition, and it allows for an additional hydrogen bond of the glucose with CD1d when in complex with the TCR. Furthermore, TCR binding causes an induced fit in both the sugar and CD1d, and we have identified the CD1d amino acids important for iNKT TCR recognition and the stability of the ternary complex. The studies show also how hydrogen bonds formed by the glucose sugar can account for the distinct binding kinetics of the TCR for this CD1d-glycolipid complex. Therefore, our studies illuminate the mechanism of glycolipid recognition for antigens from important pathogens. Invariant natural killer T (iNKT) cells are an evolutionarily conserved population of immune cells that recognize lipid antigens. A protein called a T cell receptor for antigen (TCR) on the surface of these iNKT cells recognizes lipids bound to a protein called CD1d on the surface of antigen-presenting cells. Here we describe the three-dimensional structure of the complex that forms between CD1d and the iNKT TCR together with a glycolipid antigen from the infectious bacterium Streptococcus pneumoniae, which is a common cause of bacterial meningitis in adults and is responsible for many other pneumococcal infections. We determined the three-dimensional structure of the complex by X-ray crystallography. The data obtained allow us to understand the structural requirements that make this glycolipid a potent antigen for iNKT cells, and why the TCR of these cells recognizes a particular combination of hexose sugar and diacylglycerol lipid. Moreover, by mutating CD1d and using biophysical methods to study the mutant protein complexes, we analyzed the role of the protein–protein interface between CD1d and the TCR and found that it plays an important role in the stability, but not the formation, of the trimolecular complex containing glycolipid antigen.
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影响因子：
4.8
作者：
Rauch, J;Gumperz, J;Behar, SM
通讯作者：
Behar, SM
影响因子：
5.4
作者：
Sriram, V;Du, WJ;Brutkiewicz, RR
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影响因子：
32.4
作者：
Wun KS;Cameron G;Patel O;Pang SS;Pellicci DG;Sullivan LC;Keshipeddy S;Young MH;Uldrich AP;Thakur MS;Richardson SK;Howell AR;Illarionov PA;Brooks AG;Besra GS;McCluskey J;Gapin L;Porcelli SA;Godfrey DI;Rossjohn J
通讯作者：
Rossjohn J
影响因子：
30.5
作者：
Kinjo, Yuki;Tupin, Emmanuel;Kronenberg, Mitchell
通讯作者：
Kronenberg, Mitchell
DOI：
10.1084/jem.20062342
发表时间：
2007-05-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
McCarthy C;Shepherd D;Fleire S;Stronge VS;Koch M;Illarionov PA;Bossi G;Salio M;Denkberg G;Reddington F;Tarlton A;Reddy BG;Schmidt RR;Reiter Y;Griffiths GM;van der Merwe PA;Besra GS;Jones EY;Batista FD;Cerundolo V
通讯作者：
Cerundolo V