Lysosomal Recycling Terminates CD1d-mediated Presentation of Short and Polyunsaturated Variants of the NKT Cell Lipid Antigen AlphaGalCer

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Jun 10

PMID 19506241

Citations 47

Authors

Li Bai

Yuval Sagiv

Yang Liu

Stefan Freigang

Karl O A Yu

Luc Teyton

Steven A Porcelli

Paul B Savage

Albert Bendelac

Affiliations

Soon will be listed here.

Abstract

Short or polyunsaturated lipid variants of the NKT cell antigen alpha-galactosylceramide (alphaGC) 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 alphaGC. However, in contrast with alphaGC, 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 alphaGC 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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