Defective presentation of the CD1d1-restricted natural Va14Ja18 NKT lymphocyte antigen caused by β-D-glucosylceramide synthase deficiency

Aleksandar K. Stanic, A. Dharshan De Silva, Jang June Park, Venkataraman Sriram, Shinichi Ichikawa, Yoshio Hirabyashi, Kyoko Hayakawa, Luc Van Kaer, Randy R. Brutkiewicz, Sebastian Joyce

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128 Scopus citations

Abstract

Va14Ja18 natural T (NKT) cells play an immunoregulatory role, which is controlled by a self glycolipid(s) presented by CDld. Although the synthetic antigen α-D-galactosylceramide (α-D-GalCer) stimulates all Va14Ja18 NKT cells, α-anomeric D-glycosylceramides are currently unknown in mammals. We have used β-D-GalCer-deficient mice and β-D-glucosylceramide (β-D-GlcCer)-deficient cells to define the chemical nature of a natural NKT cell antigen. β-D-GalCer-deficient mice exhibit normal NKT cell development and function, and cells from these animals potently stimulate NKT hybridomas. In striking contrast, the same hybridomas fail to react to CD1d1 expressed by a β-D-GlcCer-deficient cell line. Importantly, human β-D-GlcCer synthase cDNA transfer, and hence the biosynthesis of β-D-GlcCer, restores the recognition of mutant cells expressing CD1d1 by the Va14Ja18 NKT hybridomas. Additionally, suppression of β-D-GlcCer synthesis inhibits antigen presentation to Va14Ja18 NKT cells. The possibility that β-D-GlcCer itself is the natural NKT cell antigen was excluded because it was unable to activate NKT hybridomas in a cell-free antigen-presentation assay. These findings suggest that β-D-GlcCer may play an important role in generating and/or loading a natural Va14Ja18 NKT antigen.

Original languageEnglish (US)
Pages (from-to)1849-1854
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number4
DOIs
StatePublished - Feb 18 2003

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