title: Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C.
abstract: Invariant natural killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α-galactosylceramide, a non-mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or NPC2, resulting in the storage of multiple lipids, including glycosphingolipids. In the NPC1 mouse model, iNKT cells are virtually undetectable, which is likely due to the inability of CD1d to be loaded with the selecting ligand due to defective lysosomal function and/or CD1d trafficking. However, in this study we have found that in NPC1 patients iNKT cells are present at normal frequencies, with no phenotypic or functional differences. In addi-tion, antigen-presenting cells derived from NPC1 patients are functionally competent to present several different CD1d/iNKT-cell ligands. This further supports the hypothesis that there are different trafficking requirements for the development of murine and human iNKT cells, and a functional lysosomal/late-endosomal compartment is not required for human iNKT-cell development.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.forename: Nicholas
authors.initials: N
authors.lastname: Platt
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Danielle
authors.initials: D
authors.lastname: te Vruchte
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.forename: Natacha
authors.initials: N
authors.lastname: Veerapen
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Yanjanin
authors.forename: Louise
authors.initials: L
authors.lastname: Simmons
authors.forename: Jackie
authors.initials: J
authors.lastname: Imrie
authors.forename: James E
authors.initials: JE
authors.lastname: Wraith
authors.forename: Robin H
authors.initials: RH
authors.lastname: Lachmann
authors.forename: Ralf
authors.initials: R
authors.lastname: Hartung
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.forename: Michael
authors.initials: M
authors.lastname: Beck
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hendriksz
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008247:Lysosomes / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D052556:Niemann-Pick Disease, Type C / Q000276:immunology*
chemical_list: D055610:Antigens, CD1d; C508598:IL4 protein, human; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor