title: Cutting edge: impaired glycosphingolipid trafficking and NKT cell development in mice lacking Niemann-Pick type C1 protein.
abstract: Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal transmembrane protein involved in the cellular transport of glycosphingolipids and cholesterol that is mutated in a majority of patients with Niemann-Pick C neurodegenerative disease. We found that NPC1-deficient mice lacked Valpha14-Jalpha18 NKT cells, a major population of CD1d-restricted T cells that is conserved in humans. NPC1-deficient mice also exhibited marked defects in the presentation of Sphingomonas cell wall Ags to NKT cells and in bacterial clearance in vivo. A synthetic fluorescent alpha-glycosylceramide analog of the Sphingomonas Ag trafficked to the lysosome of wild-type cells but accumulated in the late endosome of NPC1-deficient cells. These findings reveal a blockade of lipid trafficking between endosome and lysosome as a consequence of NPC1 deficiency and suggest a common mechanism for the defects in lipid presentation and development of Valpha14-Jalpha18 NKT cells.
authors.affiliation: Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Sagiv
authors.forename: Kelly
authors.initials: K
authors.lastname: Hudspeth
authors.forename: Jochen
authors.initials: J
authors.lastname: Mattner
authors.forename: Nicolas
authors.initials: N
authors.lastname: Schrantz
authors.forename: Randi K
authors.initials: RK
authors.lastname: Stern
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhou
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018949:Antigens, CD1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055610:Antigens, CD1d; D001693:Biological Transport, Active / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology*; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D006028:Glycosphingolipids; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta