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* Departement Mécanismes Moléculaires des Infections Mycobactériennes, Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France;
Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; and
Experimental Immunology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland
CD1b-restricted T lymphocytes recognize a large diversity of mycobacterial lipids, which differ in their hydrophilic heads and the structure of their acyl appendages. Both moieties participate in the antigenicity of lipid Ags, but the structural constraints governing binding to CD1b and generation of antigenic CD1b:lipid Ag complexes are still poorly understood. Here, we investigated the structural requirements conferring antigenicity to Mycobacterium tuberculosis sulfoglycolipid Ags using a combination of CD1b:lipid binding and T cell activation assays with both living dendritic cells and plate-bound recombinant soluble CD1b. Comparison of the antigenicity of a panel of synthetic analogs, sharing the same trehalose-sulfate polar head, but differing in the structure of their acyl tails, shows that the number of C-methyl substituents on the fatty acid, the configuration of the chiral centers, and the respective localization of the two different acyl chains on the sugar moiety govern TCR recognition and T lymphocyte activation. These studies have major implications for the design of sulfoglycolipid analogs with potential use as tuberculosis subunit vaccines.
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 This work was supported by the the European Union (TB-VAC program, LSHP-CT-2003-503367, and MILD-TB LSHP-CT-2006-037326), by the Swiss National Fund Grant 3100A0-109918, and by the Agence Nationale de la Recherche emergence (France). L.F.G.-A. received a grant from the Fondation pour la Recherche Medicale.
2 J.G. and A.C. are equally contributing first authors.
3 Address correspondence and reprint requests to Dr. Germain Puzo, Institut de Pharmacologie et de Biologie Structurale/Centre National de la Recherche Scientifique, 205 Route de Narbonne, 31077 Toulouse Cedex 04, France. E-mail address: Germain.Puzo{at}ipbs.fr and Dr. Gennaro De Libero, Experimental Immunology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. E-mail address: Gennaro.DeLibero{at}unibas.ch
4 Abbreviations used in this paper: PIM, phosphatidyl myo-inositol mannoside; 
-GalCer, -galactosylceramide; Ac2, Ac3, Ac4SGL, di-, tri, tetraacylated sulfoglycolipid; CE, capillary electrophoresis; DAT/TAT, di/triacyltrehalose; DC, dendritic cell; GMM, glucose monomycolate; GroMM, glycerol monomycolate; ID, internal diameter; (c)IEF, (capillary) isoelectric focusing electrophoresis; iNKT, invariant NKT; MPM, mannosyl-β-1-phosphomycoketide; m/z, mass-to-charge ratio; PC, phosphatidylcholine; sCD1b, soluble CD1b; SGL, sulfoglycolipid.
5 The online version of this article contains supplemental material.
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