Cutting edge: impaired glycosphingolipid trafficking and NKT cell development in mice lacking Niemann-Pick type C1 protein.
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.
Sagiv
Yuval
Y
Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Hudspeth
Kelly
K
Mattner
Jochen
J
Schrantz
Nicolas
N
Stern
Randi K
RK
Zhou
Dapeng
D
Savage
Paul B
PB
Teyton
Luc
L
Bendelac
Albert
A
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*
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