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J Immunol. 2015 Aug 1;195(3):924-33. doi: 10.4049/jimmunol.1500070. Epub 2015 Jun 15.

A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-γ Production.

Author information

1
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037;
2
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
3
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
4
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
5
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033;
6
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461.
7
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037; mitch@liai.org.

Abstract

In this article, we characterize a novel Ag for invariant NKT (iNKT) cells capable of producing an especially robust Th1 response. This glycosphingolipid, DB06-1, is similar in chemical structure to the well-studied α-galactosylceramide (αGalCer), with the only change being a single atom: the substitution of a carbonyl oxygen with a sulfur atom. Although DB06-1 is not a more effective Ag in vitro, the small chemical change has a marked impact on the ability of this lipid Ag to stimulate iNKT cells in vivo, with increased IFN-γ production at 24 h compared with αGalCer, increased IL-12, and increased activation of NK cells to produce IFN-γ. These changes are correlated with an enhanced ability of DB06-1 to load in the CD1d molecules expressed by dendritic cells in vivo. Moreover, structural studies suggest a tighter fit into the CD1d binding groove by DB06-1 compared with αGalCer. Surprisingly, when iNKT cells previously exposed to DB06-1 are restimulated weeks later, they have greatly increased IL-10 production. Therefore, our data are consistent with a model whereby augmented and or prolonged presentation of a glycolipid Ag leads to increased activation of NK cells and a Th1-skewed immune response, which may result, in part, from enhanced loading into CD1d. Furthermore, our data suggest that strong antigenic stimulation in vivo may lead to the expansion of IL-10-producing iNKT cells, which could counteract the benefits of increased early IFN-γ production.

PMID:
26078271
PMCID:
PMC4506857
DOI:
10.4049/jimmunol.1500070
[Indexed for MEDLINE]
Free PMC Article

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