Cutting edge: impaired glycosphingolipid trafficking and NKT cell development in mice lacking Niemann-Pick type C1 protein

J Immunol. 2006 Jul 1;177(1):26-30. doi: 10.4049/jimmunol.177.1.26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics
  • Antigens, CD1 / genetics
  • Antigens, CD1 / metabolism
  • Antigens, CD1 / physiology
  • Antigens, CD1d
  • Biological Transport, Active / genetics
  • Biological Transport, Active / immunology
  • Cell Differentiation / genetics*
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Glycosphingolipids / antagonists & inhibitors
  • Glycosphingolipids / immunology
  • Glycosphingolipids / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology*
  • Lymphopenia / genetics*
  • Lymphopenia / immunology
  • Lymphopenia / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Niemann-Pick C1 Protein
  • Niemann-Pick Diseases / genetics
  • Niemann-Pick Diseases / immunology
  • Niemann-Pick Diseases / pathology
  • Proteins / genetics*
  • Proteins / physiology
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology*

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • CD1D protein, human
  • Glycosphingolipids
  • Intracellular Signaling Peptides and Proteins
  • Niemann-Pick C1 Protein
  • Npc1 protein, mouse
  • Proteins
  • Receptors, Antigen, T-Cell, alpha-beta