The Journal of Experimental Medicine
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Published online 23 February 2004 doi:10.1084/jem.20031097
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 5, 649-659
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Diacylated Sulfoglycolipids Are Novel Mycobacterial Antigens Stimulating CD1-restricted T Cells during Infection with Mycobacterium tuberculosis

Martine Gilleron1, Steffen Stenger2, Zaima Mazorra3, Frederick Wittke2, Sabrina Mariotti3, Gabriele Böhmer4, Jacques Prandi1, Lucia Mori3, Germain Puzo1, and Gennaro De Libero3

1 Département Mécanismes Moléculaires des Infections Mycobactériennes, Institut de Pharmacologie et de Biologie Structurale du CNRS, Toulouse 31077, France
2 Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Erlangen 91054, Germany
3 Experimental Immunology, Department of Research, University Hospital, Basel CH-4031, Switzerland
4 Bezirksklinikum Obermain, Kutzenberg, Ebensfeld 96248, Germany

Address correspondence to Gennaro De Libero, Experimental Immunology, Department of Research, University Hospital, Hebelstrasse 20, Basel CH-4031, Switzerland. Phone: 41-61-265-23-27; Fax: 41-61-265-23-50; email: Gennaro.DeLibero{at}unibas.ch; or Germain Puzo, Institut de Pharmacologie et de Biologie Structurale du CNRS, Département Mécanismes Moléculaires des Infections Mycobactériennes, 205 route de Narbonne, Toulouse 31077, Cedex 4, France. Phone: 33-56-1175504; Fax: 33-561175505; email: Germain.Puzo{at}ipbs.fr

Mycobacterial lipids comprise a heterogeneous group of molecules capable of inducing T cell responses in humans. To identify novel antigenic lipids and increase our understanding of lipid-mediated immune responses, we established a panel of T cell clones with different lipid specificities. Using this approach we characterized a novel lipid antigen belonging to the group of diacylated sulfoglycolipids purified from Mycobacterium tuberculosis. The structure of this sulfoglycolipid was identified as 2-palmitoyl or 2-stearoyl-3-hydroxyphthioceranoyl-2'-sulfate-{alpha}-{alpha}'-D-trehalose (Ac2SGL). Its immunogenicity is dependent on the presence of the sulfate group and of the two fatty acids. Ac2SGL is mainly presented by CD1b molecules after internalization in a cellular compartment with low pH. Ac2SGL-specific T cells release interferon {gamma}, efficiently recognize M. tuberculosis–infected cells, and kill intracellular bacteria. The presence of Ac2SGL-responsive T cells in vivo is strictly dependent on previous contact with M. tuberculosis, but independent from the development of clinically overt disease. These properties identify Ac2SGL as a promising candidate to be tested in novel vaccines against tuberculosis.

Key Words: vaccination • intracellular bacteria • protection • cytotoxic CD8+ T cells • lipids

M. Gilleron, S. Stenger, and Z. Mazorra contributed equally to this work.

The online version of this article contains supplemental material.

Z. Mazorra's present address is Center of Molecular Immunology, P.O. Box 16040, Havana, 11600 Cuba.

Abbreviations used in this paper: 1H NMR, proton nuclear magnetic resonance; Ac2SGL, 2-palmitoyl or 2-stearoyl-3-hydroxyphthioceranoyl-2'-sulfate-{alpha}-{alpha}'-D-trehalose; BCG, bacillus Calmette Guérin; MALDI-Tof-MS, matrix-assisted laser desorption/ionization-time of flight-mass spectrometry; m/z, mass/charge; NMR, nuclear magnetic resonance; PIM, phosphatidyl-myo-inositol mannosides; PPD, purified protein derivative of M. tuberculosis; SGL, sulfoglycolipids.


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