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J. Biol. Chem., Vol. 278, Issue 48, 47508-47515, November 28, 2003

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Structural Features of the Acyl Chain Determine Self-phospholipid Antigen Recognition by a CD1d-restricted Invariant NKT (iNKT) Cell^*

Joyce Rauch, Jenny Gumperz, Cheryl Robinson, Markus Sköld, Chris Roy, David C. Young¶, Michel Lafleur||, D. Branch Moody, Michael B. Brenner, Catherine E. Costello¶, and Samuel M. Behar**

From the Division of Rheumatology, The Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada, the Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115, ^¶The Mass Spectrometry Resource, Dept. of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, and the ^||Department of Chemistry, Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Little is known about the antigen specificity of CD1d-restricted T cells, except that they frequently recognize CD1d-expressing antigen-presenting cells in the absence of exogenous antigen. We previously demonstrated that the 24.8.A iNKT cell hybridoma was broadly reactive with CD1d-transfected cell lines and recognized the polar lipid fraction of a tumor cell extract. In the present study, the antigen recognized by the 24.8.A iNKT cell hybridoma was purified to homogeneity and identified as palmitoyl-oleoyl-sn-glycero-3-phosphoethanolamine (16:0–18:1 PE). The 24.8.A iNKT cell hybridoma recognized synthetic 16:0-18:1[cis] PE, confirming that this phospholipid is antigenic. Recognition correlated with the degree of unsaturation of the acyl chains. Using a panel of synthetic PEs, the 24.8.A iNKT cell hybridoma was shown to be activated by PEs that contained at least one unsaturated acyl chain. The configuration of the double bonds was important, as the 24.8.A iNKT cell hybridoma recognized unsaturated acyl chains in the cis, but not the trans, configuration. PEs with multiple double bonds were recognized better than those with a single double bond, and increasing acyl chain unsaturation correlated with increased binding of PE to CD1d. These data illustrate the potential importance of the acyl chain structure for phospholipid antigen binding to CD1d.

Received for publication, July 24, 2003 , and in revised form, September 3, 2003.

^* This work was supported by operating grants from the Arthritis Society of Canada (to J. R.), the Canadian Institutes of Health Research (to J. R.), a Schering Traveling Fellowship from the Canadian Society for Clinical Investigation (to J. R.), the American College of Rheumatology Research and Education Foundation (to D. B. M.), NIAID, National Institutes of Health Grant R01-AI49313, the Arthritis Foundation (to S. M. B.), and the National Center for Research Resources, National Institutes of Health (to C. E. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Smith Building, Rm. 516, One Jimmy Fund Way, Boston, MA 02115. Tel.: 617-525-1033; Fax: 617-525-1010; E-mail: sbehar{at}rics.bwh.harvard.edu.

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