期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 25, 页码 10254-10259出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0901228106
关键词
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资金
- National Institutes of Health [PO1 AI053725]
- LT and PBS [AI45889]
- University of Chicago Digestive Diseases Research Core Center [P30 DK42086]
- Cancer Research Institute
Short or polyunsaturated lipid variants of the NKT cell antigen alpha-galactosylceramide (alpha GC) exhibit decreased potency and a Th2 bias in vivo despite conserved TCR contact residues and stable binding to CD1d at neutral and acidic pH. Using reagents to directly visualize lipids in their free or CD1d-bound form, we determined that, contrary to predictions, these lipids reached the lysosome better than alpha GC. However, in contrast with alpha GC, they loaded CD1d at the cell surface and underwent immediate pH-dependent dissociation upon recycling to the lysosome. In cell-free assays, ultrafast dissociation of preformed complexes could be induced at acidic pH only when free competitor lipids were added, suggesting active lipid displacement. These findings provide a common cell biological explanation for the decreased stimulatory properties of short and polyunsaturated alpha GC variants. They also suggest that direct lipid displacement is a potent mechanism underlying highly dynamic lipid exchange reactions in the lysosomal compartment that shape the repertoire of lipids associated with CD1d.
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