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PMID: 12576547 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 4 ·2003-02-18 ·Pages 1849-54

Stanic AK, De Silva AD, Park JJ, Sriram V, Ichikawa S, Hirabyashi Y, Hayakawa K, Van Kaer L, Brutkiewicz RR, Joyce S

Abstract

Va14Ja18 natural T (NKT) cells play an immunoregulatory role, which is controlled by a self glycolipid(s) presented by CD1d. Although the synthetic antigen alpha-D-galactosylceramide (alpha-D-GalCer) stimulates all Va14Ja18 NKT cells, alpha-anomeric D-glycosylceramides are currently unknown in mammals. We have used beta-D-GalCer-deficient mice and beta-D-glucosylceramide (beta-D-GlcCer)-deficient cells to define the chemical nature of a natural NKT cell antigen. beta-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 beta-D-GlcCer-deficient cell line. Importantly, human beta-D-GlcCer synthase cDNA transfer, and hence the biosynthesis of beta-D-GlcCer, restores the recognition of mutant cells expressing CD1d1 by the Va14Ja18 NKT hybridomas. Additionally, suppression of beta-D-GlcCer synthesis inhibits antigen presentation to Va14Ja18 NKT cells. The possibility that beta-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 beta-D-GlcCer may play an important role in generating and/or loading a natural Va14Ja18 NKT antigen.

MeSH Terms
Animals Antigens, CD1/immunology Antigens, CD1d Base Sequence Cell Line Chromatography, Thin Layer DNA Primers Enzyme-Linked Immunosorbent Assay Glucosyltransferases/deficiency,genetics Hybridomas Killer Cells, Natural/immunology Mice Mice, Knockout
Chemicals
Antigens, CD1 Antigens, CD1d CD1D protein, human DNA Primers Glucosyltransferases ceramide glucosyltransferase
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Stanic Aleksandar K
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
De Silva A Dharshan
Park Jang-June
Sriram Venkataraman
Ichikawa Shinichi
Hirabyashi Yoshio
Hayakawa Kyoko
Van Kaer Luc
Brutkiewicz Randy R
Joyce Sebastian
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0430327100
Published
2003-02-18
Epub
2003-00-07
Pages
1849-54
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC149922
Subset
IM
Grants
NIAID NIH HHS · R01 AI046455 · United States
NIAID NIH HHS · R56 AI046455 · United States
NIAID NIH HHS · AI46455 · United States
NIAID NIH HHS · R21 AI042284 · United States
NIAID NIH HHS · R01 AI042284 · United States
NIAID NIH HHS · AI42284 · United States
External Links
PubMed source DOI: 10.1073/pnas.0430327100 PMC Full Text View journal details
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