title: Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism.
abstract: Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme beta-galactosidase (betaGal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in betaGal-/- and NPC2-/- mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders.
authors.affiliation: Experimental Immunology, Department of Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Schümann
authors.forename: Federica
authors.initials: F
authors.lastname: Facciotti
authors.forename: Luigi
authors.initials: L
authors.lastname: Panza
authors.forename: Mario
authors.initials: M
authors.lastname: Michieletti
authors.forename: Federica
authors.initials: F
authors.lastname: Compostella
authors.forename: Anthony
authors.initials: A
authors.lastname: Collmann
authors.forename: Lucia
authors.initials: L
authors.lastname: Mori
authors.forename: Gennaro
authors.initials: G
authors.lastname: De Libero
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D018949:Antigens, CD1 / Q000032:analysis / Q000378:metabolism; D055610:Antigens, CD1d; D015704:CD4 Antigens / Q000032:analysis / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005699:Galactosylceramides / Q000276:immunology / Q000378:metabolism; D005915:Globosides / Q000276:immunology; D006017:Glycolipids / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000276:immunology*; D052439:Lipid Metabolism Disorders / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014281:Trihexosylceramides / Q000276:immunology; D033921:Vesicular Transport Proteins / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D005699:Galactosylceramides; D005915:Globosides; D006017:Glycolipids; C497045:Npc2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D014281:Trihexosylceramides; D033921:Vesicular Transport Proteins; C493154:alpha-galactosylceramide; C514781:isoglobotrihexosylceramide; D017485:1-Deoxynojirimycin; C059896:miglustat; D001616:beta-Galactosidase