title: Globotriaosylceramide inhibits iNKT-cell activation in a CD1d-dependent manner.
abstract: Globotriaosylceramide (Gb3) is a glycosphingolipid present in cellular membranes that progressively accumulates in Fabry disease. Invariant Natural Killer T (iNKT) cells are a population of lipid-specific T cells that are phenotypically and functionally altered in Fabry disease. The mechanisms responsible for the iNKT-cell alterations in Fabry disease are not well understood. Here, we analyzed the effect of Gb3 on CD1d-mediated iNKT-cell activation in vitro using human cells and in vivo in the mouse model. We found that Gb3 competes with endogenous and exogenous antigens for CD1d binding, thereby reducing the activation of iNKT cells. This effect was exerted by a reduction in the amount of stimulatory CD1d:α-GalCer complexes in the presence of Gb3 as demonstrated by using an mAb specific for the complex. We also found that administration of Gb3 delivered to the same APC as α-GalCer, induces reduced iNKT-cell activation in vivo. This work highlights the complexity of iNKT-cell activation and the importance of nonantigenic glycosphingolipids in the modulation of this process.
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Catia S
authors.initials: CS
authors.lastname: Pereira
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Clara
authors.initials: C
authors.lastname: Sa-Miranda
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.|Experimental Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Gennaro
authors.initials: G
authors.lastname: De Libero
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.|Experimental Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mori
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|Aveiro Health Sciences Program, University of Aveiro, Aveiro, Portugal.
authors.forename: Maria Fatima
authors.initials: MF
authors.lastname: Macedo
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology*; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D014281:Trihexosylceramides / Q000276:immunology*
chemical_list: D055610:Antigens, CD1d; D014281:Trihexosylceramides; C018549:globotriaosylceramide
keywords: CD1d; Fabry disease; Globotriaosylceramide (Gb3); iNKT cells; lysosomal storage diseases