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Cutting Edge: Nonglycosidic CD1d Lipid Ligands Activate Human and Murine Invariant NKT Cells¹

Jonathan D. Silk^2,*, Mariolina Salio^2,*, B. Gopal Reddy^2,, Dawn Shepherd^*, Uzi Gileadi^*, James Brown, S. Hajar Masri^*, Paolo Polzella^*, Gerd Ritter, Gurdyal S. Besra^¶, E. Yvonne Jones, Richard R. Schmidt and Vincenzo Cerundolo^3,*

^* Tumour Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; Fachbereich Chemie, Universität Konstanz, Konstanz, Germany; Cancer Research U.K. Receptor Structure Research Group, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and ^¶ School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

Invariant NKT cells (iNKT cells) recognize CD1d/glycolipid complexes. We demonstrate that the nonglycosidic compound threitolceramide efficiently activates iNKT cells, resulting in dendritic cell (DC) maturation and the priming of Ag-specific T and B cells. Threitolceramide-pulsed DCs are more resistant to iNKT cell-dependent lysis than -galactosylceramide-pulsed DCs due to the weaker affinity of the human iNKT TCR for CD1d/ threitolceramide than CD1d/-galactosylceramide complexes. iNKT cells stimulated with threitolceramide also recover more quickly from activation-induced anergy. Kinetic and functional experiments showed that shortening or lengthening the threitol moiety by one hydroxymethylene group modulates ligand recognition, as human and murine iNKT cells recognize glycerolceramide and arabinitolceramide differentially. Our data broaden the range of potential iNKT cell agonists. The ability of these compounds to assist the priming of Ag-specific immune responses while minimizing iNKT cell-dependent DC lysis makes them attractive adjuvants for vaccination strategies.

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.

¹ Funding for this work was provided by the Ludwig Institute for Cancer Research and Cancer Research U.K. Grants C399/A2291 (to V.C.) and C375 (to E.Y.J.) and the Royal Society Wolfson Research Merit Award, a Personal Research Chair from James Bardrick, and a former Lister Institute-Jenner Research Fellowship (to G.S.B.).

² J.D.S., M.S., and B.G.R. contributed equally to the work.

³ Address correspondence and reprint requests to Dr. Vincenzo Cerundolo, Tumour Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. E-mail address: vincenzo.cerundolo{at}imm.ox.ac.uk

⁴ Abbreviations used in this paper: iNKT cell, invariant NK T cell; -GalCer, -galactosylceramide; AraCer, arabinitolceramide; DC, dendritic cell; GlyCer, glycerolceramide; H-bond, hydrogen bond; hCD1d, human CD1d; MPL, monophosphoryl lipid A; ThrCer, threitolceramide.