title: Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases.
abstract: Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to alpha-galactosylceramide (alpha-GalCer) and reduced iNKT cell-mediated lysis of wild-type targets loaded with alpha-GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4(+) T cell responses were generally unaffected, processing of a lysosome-dependent analogue of alpha-GalCer was impaired in all the strains of mice tested. These data suggest that GSL storage may result in alterations in thymic selection of iNKT cells caused by impaired presentation of selecting ligands.
authors.affiliation: Weatherall Institute of Molecular Medicine, Tumour Immunology Group, John Radcliffe Hospital, Oxford OX3 9DS, England, UK.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Gadola
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Silk
authors.forename: Aruna
authors.initials: A
authors.lastname: Jeans
authors.forename: Petr A
authors.initials: PA
authors.lastname: Illarionov
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Raymond
authors.initials: R
authors.lastname: Dwek
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000378:metabolism; D006028:Glycosphingolipids / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008024:Ligands; D016464:Lysosomal Storage Diseases / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D006028:Glycosphingolipids; D008024:Ligands; C493154:alpha-galactosylceramide