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J Biol Chem. 2015 Jul 10;290(28):17206-17. doi: 10.1074/jbc.M115.654814. Epub 2015 May 27.

Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation.

Author information

1
From the Division of Cell Biology and Division of Developmental Immunology,La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, the Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037.
2
From the Division of Cell Biology and.
3
Division of Developmental Immunology,La Jolla Institute for Allergy and Immunology, La Jolla, California 92037.
4
the Laboratory for Medicinal Chemistry, Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium.
5
the Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, and.
6
the Department of Chemistry, Hunter College of City University of New York, New York, New York 10021.
7
the Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016.
8
Division of Developmental Immunology,La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, the Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037.
9
From the Division of Cell Biology and the Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium dzajonc@lji.org.

Abstract

The ability of different glycosphingolipids (GSLs) to activate type I natural killer T cells (NKT cells) has been known for 2 decades. The possible therapeutic use of these GSLs has been studied in many ways; however, studies are needed in which the efficacy of promising GSLs is compared under identical conditions. Here, we compare five unique GSLs structurally derived from α-galactosylceramide. We employed biophysical and biological assays, as well as x-ray crystallography to study the impact of the chemical modifications of the antigen on type I NKT cell activation. Although all glycolipids are bound by the T cell receptor of type I NKT cells in real time binding assays with high affinity, only a few activate type I NKT cells in in vivo or in vitro experiments. The differences in biological responses are likely a result of different pharmacokinetic properties of each lipid, which carry modifications at different parts of the molecule. Our results indicate a need to perform a variety of assays to ascertain the therapeutic potential of type I NKT cell GSL activators.

KEYWORDS:

T cell receptor (TCR); cytokine induction; glycolipid structure; immunology; protein crystallization; surface plasmon resonance (SPR)

PMID:
26018083
PMCID:
PMC4498060
DOI:
10.1074/jbc.M115.654814
[Indexed for MEDLINE]
Free PMC Article

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