title: Glycolipids that elicit IFN-γ-biased responses from natural killer T cells.
abstract: Natural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, α-galactosyl ceramide (αGalCer), is a potential anticancer agent whose activity depends upon IFN-γ secretion. We report two analogs of αGalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-γ that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-γ-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility.
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Tyznik
authors.forename: Elisa
authors.initials: E
authors.lastname: Farber
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.forename: Alysia
authors.initials: A
authors.lastname: Birkholz
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.forename: Sampada
authors.initials: S
authors.lastname: Chitale
authors.forename: Regina
authors.initials: R
authors.lastname: So
authors.forename: Pooja
authors.initials: P
authors.lastname: Arora
authors.forename: Archana
authors.initials: A
authors.lastname: Khurana
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D055610:Antigens, CD1d / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006017:Glycolipids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D055610:Antigens, CD1d; D000970:Antineoplastic Agents; D005699:Galactosylceramides; D006017:Glycolipids; C493154:alpha-galactosylceramide; D007371:Interferon-gamma