title: Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen alphaGalCer.
abstract: Short or polyunsaturated lipid variants of the NKT cell antigen alpha-galactosylceramide (alphaGC) exhibit decreased potency and a Th2 bias in vivo despite conserved TCR contact residues and stable binding to CD1d at neutral and acidic pH. Using reagents to directly visualize lipids in their free or CD1d-bound form, we determined that, contrary to predictions, these lipids reached the lysosome better than alphaGC. However, in contrast with alphaGC, they loaded CD1d at the cell surface and underwent immediate pH-dependent dissociation upon recycling to the lysosome. In cell-free assays, ultrafast dissociation of preformed complexes could be induced at acidic pH only when free competitor lipids were added, suggesting active lipid displacement. These findings provide a common cell biological explanation for the decreased stimulatory properties of short and polyunsaturated alphaGC variants. They also suggest that direct lipid displacement is a potent mechanism underlying highly dynamic lipid exchange reactions in the lysosomal compartment that shape the repertoire of lipids associated with CD1d.
authors.affiliation: Department of Pathology, Howard Hughes Medical Institute, Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.forename: Yuval
authors.initials: Y
authors.lastname: Sagiv
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Stefan
authors.initials: S
authors.lastname: Freigang
authors.forename: Karl O A
authors.initials: KO
authors.lastname: Yu
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology*; D018949:Antigens, CD1 / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D011992:Endosomes / Q000276:immunology; D005699:Galactosylceramides / Q000276:immunology*; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000648:ultrastructure
chemical_list: D000941:Antigens; D018949:Antigens, CD1; D005699:Galactosylceramides; C103873:KRN 7000