title: A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-γ Production.
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.
authors.affiliation: 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;
authors.forename: Alysia M
authors.initials: AM
authors.lastname: Birkholz
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wingender
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Archana
authors.initials: A
authors.lastname: Khurana
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Sonja
authors.initials: S
authors.lastname: Zahner
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors.forename: Petr A
authors.initials: PA
authors.lastname: Illarionov
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033;
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033;
authors.forename: Michelle
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033;
authors.forename: Weiming
authors.identifier: http://orcid.org/0000-0002-4780-7157
authors.initials: W
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.affiliation: 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.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology; D001665:Binding Sites / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology*; D006028:Glycosphingolipids / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; C000602278:DB06-1 compound; D005699:Galactosylceramides; D006028:Glycosphingolipids; C556062:IL10 protein, mouse; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma