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-Galactosylceramide to Break Tolerance against Self Antigen and Elicit Antiviral Immunity1
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* Equipe d’accueil 4054 Université Paris-Descartes, Ecole Nationale Vétérinaire d’Alfort, Paris, France;
Unité d’Immunologie Biologique, Hopital Européen Georges Pompidou, Assistance Publique des Höpitaux de Paris, Paris, France;
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Unité d’Immunité Cellulaire Antivirale, Département d’Immunologie, Institut Pasteur, Paris, France;
¶ Unité Mixte de Recherche 144, Institut Curie/Centre National de la Recherche Scientifique, Traffic and Signaling Laboratory, Paris, France;
|| Centre National de la Recherche Scientifique Fédération de Recherche 2444, Université Paris 5 René Descartes, Hopital Necker, Paris, France; and
# Unité Mixte de Recherche-S872 Centre de Recherche des Cordeliers, France
The nontoxic B subunit of Shiga toxin (STxB) targets in vivo Ag to dendritic cells that preferentially express the glycolipid Gb3 receptor. After administration of STxB chemically coupled to OVA (STxB-OVA) or E7, a polypeptide derived from HPV, in mice, we showed that the addition of 
-galactosylceramide (-GalCer) resulted in a dramatic improvement of the STxB Ag delivery system, as reflected by the more powerful and longer lasting CD8+ T cell response observed even at very low dose of immunogen (50 ng). This synergy was not found with other adjuvants (CpG, poly(I:C), IFN-) also known to promote dendritic cell maturation. With respect to the possible mechanism explaining this synergy, mice immunized with -GalCer presented in vivo the OVA257–264/Kb complex more significantly and for longer period than mice vaccinated with STxB alone or mixed with other adjuvants. To test whether this vaccine could break tolerance against self Ag, OVA transgenic mice were immunized with STxB-OVA alone or mixed with -GalCer. Although no CTL induction was observed after immunization of OVA transgenic mice with STxB-OVA, tetramer assay clearly detected specific anti-OVA CD8+ T cells in 8 of 11 mice immunized with STxB-OVA combined with -GalCer. In addition, vaccination with STxB-OVA and -GalCer conferred strong protection against a challenge with vaccinia virus encoding OVA with virus titers in the ovaries reduced by 5 log compared with nonimmunized mice. STxB combined with -GalCer therefore appears as a promising vaccine strategy to more successfully establish protective CD8+ T cell memory against intracellular pathogens and tumors.
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 Association pour la Recherche sur le Cancer, the Fondation de France, the Canceropole d’Ile de France, Centre d’Investigation Clinique en Biothérapie (AP-HP/INSERM), the European Economic Community "Cancer Immunotherapy," and Pôle de competitivité "Projet Immucan." B.V. is a fellow of the Fondation de France.
2 O.A., B.V., and L.F. contributed equally to this work.
3 L.J. and E.T. were the principal investigators.
4 Address correspondence and reprint requests to Dr. Eric Tartour, Hopital Européen Georges Pompidou, Unité d’Immunologie Biologique, 20 Rue Leblanc 75908 Paris Cedex 15, France. E-mail address: eric.tartour{at}egp.aphp.fr
5 Abbreviations used in this paper: DC, dendritic cell; -GalCer, -galactosylceramide; STxB, nontoxic B subunit of Shiga toxin; TG, transgenic; VSV, vesicular stomatitis virus; VV, vaccinia virus.
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