Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis

被引：89

作者：

Aspeslagh, Sandrine ^{[2
]}

Li, Yali ^{[1
]}

Yu, Esther Dawen ^{[1
]}

Pauwels, Nora ^{[3
]}

Trappeniers, Matthias ^{[3
]}

Girardi, Enrico ^{[1
]}

Decruy, Tine ^{[2
]}

Van Beneden, Katrien ^{[2
]}

Venken, Koen ^{[2
]}

Drennan, Michael ^{[2
]}

Leybaert, Luc ^{[4
]}

Wang, Jing ^{[1
]}

Franck, Richard W. ^{[5
]}

Van Calenbergh, Serge ^{[3
]}

Zajonc, Dirk M. ^{[1
]}

Elewaut, Dirk ^{[2
]}

机构：

[1] La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA

[2] Univ Ghent, Dept Rheumatol, Fac Med & Hlth Sci, Lab Mol Immunol & Inflammat, B-9000 Ghent, Belgium

[3] Univ Ghent, Fac Pharmaceut Sci, Med Chem Lab, B-9000 Ghent, Belgium

[4] Univ Ghent, Fac Med & Hlth Sci, Dept Basic Med Sci, Physiol Grp, B-9000 Ghent, Belgium

[5] CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA

来源：

EMBO JOURNAL | 2011年 / 30卷 / 11期

关键词：

CD1d; glycolipids; iNKT cells; DENDRITIC CELLS; NKT CELLS; GALACTOSYLCERAMIDE; RECOGNITION; ACTIVATION; GAMMA; GLYCOLIPIDS; DEFICIENT; RESPONSES; ANALOG;

D O I：

10.1038/emboj.2011.145

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Invariant natural killer T (iNKT) cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. Here, we report the structure and function of a novel class of aromatic alpha-galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior tumour protection in vivo. The strength of the Thl response correlates well with enhanced lipid binding to CD1d as a result of an induced fit mechanism that binds the aromatic substitution as a third anchor, in addition to the two lipid chains. This induced fit is in contrast to another Th1-biasing glycolipid, alpha-C-GalCer, whose CD1d binding follows a conventional key-lock principle. These findings highlight the previously unexploited flexibility of CD1d in accommodating galactose-modified glycolipids and broaden the range of glycolipids that can stimulate iNKT cells. We speculate that glycolipids can be designed that induce a similar fit, thereby leading to superior and more sustained iNKT cell responses in vivo. The EMBO Journal (2011) 30, 2294-2305. doi:10.1038/emboj.2011.145; Published online 6 May 2011

引用

页码：2294 / 2305

页数：12

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