title: Cutting edge: nonglycosidic CD1d lipid ligands activate human and murine invariant NKT cells.
abstract: Invariant NKT cells (iNKT cells) recognize CD1d/glycolipid complexes. We demonstrate that the nonglycosidic compound threitolceramide efficiently activates iNKT cells, resulting in dendritic cell (DC) maturation and the priming of Ag-specific T and B cells. Threitolceramide-pulsed DCs are more resistant to iNKT cell-dependent lysis than alpha-galactosylceramide-pulsed DCs due to the weaker affinity of the human iNKT TCR for CD1d/ threitolceramide than CD1d/alpha-galactosylceramide complexes. iNKT cells stimulated with threitolceramide also recover more quickly from activation-induced anergy. Kinetic and functional experiments showed that shortening or lengthening the threitol moiety by one hydroxymethylene group modulates ligand recognition, as human and murine iNKT cells recognize glycerolceramide and arabinitolceramide differentially. Our data broaden the range of potential iNKT cell agonists. The ability of these compounds to assist the priming of Ag-specific immune responses while minimizing iNKT cell-dependent DC lysis makes them attractive adjuvants for vaccination strategies.
authors.affiliation: Tumour Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Silk
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: B Gopal
authors.initials: BG
authors.lastname: Reddy
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.forename: S Hajar
authors.initials: SH
authors.lastname: Masri
authors.forename: Paolo
authors.initials: P
authors.lastname: Polzella
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Richard R
authors.initials: RR
authors.lastname: Schmidt
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D017951:Antigen Presentation; D018949:Antigens, CD1 / Q000276:immunology* / Q000378:metabolism; D055610:Antigens, CD1d; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D020349:Surface Plasmon Resonance; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D002518:Ceramides; D005699:Galactosylceramides; D008024:Ligands; D013402:Sugar Alcohols; C493154:alpha-galactosylceramide; C003460:threitol