Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals
- Anneliese O. Speak*,
- Mariolina Salio†,
- David C. A. Neville‡,
- Josette Fontaine§,
- David A. Priestman*,
- Nick Platt¶,
- Tanya Heare‡,
- Terry D. Butters‡,
- Raymond A. Dwek‡,
- Francois Trottein§,
- Mark A. Exley‖,
- Vincenzo Cerundolo†, and
- Frances M. Platt*,**
- *Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom;
- †Weatherall Institute of Molecular Medicine, Tumour Immunology Group, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;
- ‡Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom;
- §Institut National de la Santé et de la Recherche Médicale, Unité 547, Institut Pasteur de Lille, 59019 Lille, France;
- ¶School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, United Kingdom; and
- ‖Division of Haematology and Oncology, Beth Israel Deaconess Medical Centre, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215
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Edited by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved January 5, 2007 (received for review August 22, 2006)
Abstract
Development of invariant natural killer T (iNKT) cells requires the presentation of lipid ligand(s) by CD1d molecules in the thymus. The glycosphingolipid (GSL) isoglobotrihexosylceramide (iGb3) has been proposed as the natural iNKT cell-selecting ligand in the thymus and to be involved in peripheral activation of iNKT cells by dendritic cells (DCs). However, there is no direct biochemical evidence for the presence of iGb3 in mouse or human thymus or DCs. Using a highly sensitive HPLC assay, the only tissue where iGb3 could be detected in mouse was the dorsal root ganglion (DRG). iGb3 was not detected in other mouse or any human tissues analyzed, including thymus and DCs. Even in mutant mice that store isoglobo-series GSLs in the DRG, we were still unable to detect these GSLs in the thymus. iGb3 is therefore unlikely to be a physiologically relevant iNKT cell-selecting ligand in mouse and humans. A detailed study is now warranted to better understand the nature of iNKT cell-selecting ligand(s) in vivo.
Footnotes
- **To whom correspondence should be addressed. E-mail: frances.platt{at}pharm.ox.ac.uk
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Author contributions: A.O.S., M.S., D.C.A.N., D.A.P., F.T., V.C., and F.M.P. designed research; A.O.S., M.S., J.F., D.A.P., N.P., and T.H. performed research; N.P., T.D.B., R.A.D., F.T., M.A.E., and V.C. contributed new reagents/analytic tools; A.O.S., M.S., D.C.A.N., J.F., D.A.P., T.H., F.T., V.C., and F.M.P. analyzed data; and A.O.S., M.S., D.A.P., M.A.E., V.C., and F.M.P. wrote the paper.The authors declare no conflict of interest.
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The authors declare no conflict of interest.
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This article is a PNAS direct submission.
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See Commentary on page 5713.
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↵ †† GSL abbreviations are according to the International Union of Pure and Applied Chemistry–International Union of Biochemistry and Molecular Biology Commission (1977).
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This article contains supporting information online at www.pnas.org/cgi/content/full/0607285104/DC1.
- Abbreviations:
- NKT,
- natural killer T;
- iNKT,
- invariant NKT;
- GSL,
- glycosphingolipid;
- iGb3,
- isoglobotrihexosylceramide;
- DC,
- dendritic cell;
- DRG,
- dorsal root ganglion;
- SH,
- Sandhoff disease;
- hexb−/−,
- β-hexosaminidase A and B deficient;
- β-hex,
- β-hexosaminidase;
- Gb3,
- globotrihexosylceramide;
- Gb4,
- globotetrahexosylceramide;
- iGb4,
- isoglobotetrahexosylceramide;
- iGb3S,
- iGb3 synthase;
- Gal,
- galactose;
- Galα1–3,
- α1–3-linked Gal;
- LacCer,
- lactosylceramide;
- Ggta1,
- α1–3 galactosyltransferase;
- α-Gal A−/−,
- deficient in α-galactosidase A;
- NP-HPLC,
- normal-phase HPLC;
- 2AA,
- anthranilic acid;
- Q-PCR,
- quantitative PCR;
- αGalCer,
- α-galactosylceramide.
- © 2007 by The National Academy of Sciences of the USA
