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Infection and Immunity, June 2006, p. 3396-3407, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.02086-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

High Frequency of CD4+ T Cells Specific for the TB10.4 Protein Correlates with Protection against Mycobacterium tuberculosis Infection

Sandra Hervas-Stubbs,1,2,{dagger} Laleh Majlessi,1,2,{dagger} Marcela Simsova,3 Jana Morova,3 Marie-Jesus Rojas,1,2 Clémence Nouzé,1,2 Priscille Brodin,4 Peter Sebo,3 and Claude Leclerc1,2*

Institut Pasteur, Unité de Biologie des Régulations Immunitaires, Paris F-75015, France,1 INSERM, E 352, Paris F-75015, France,2 Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic,3 Institut Pasteur, Unité de Génétique Moléculaire Bactérienne, Paris F-75015, France4

Received 28 December 2005/ Returned for modification 1 February 2006/ Accepted 23 March 2006

TB10.4 is a newly identified antigen of Mycobacterium tuberculosis recognized by human and murine T cells upon mycobacterial infection. Here, we show that immunization with Mycobacterium bovis BCG induces a strong, genetically controlled, Th1 immune response against TB10.4 in mice. BALB/c and C57BL/6 strains behave as high and low responders to TB10.4 protein, respectively. The TB10.4:74-88 peptide was identified as an immunodominant CD4+ T-cell epitope for H-2d mice. Since recent results, as well as the present study, have raised interest in TB10.4 as a subunit vaccine, we analyzed immune responses induced by this antigen delivered by a new vector, the adenylate cyclase (CyaA) of Bordetella pertussis. CyaA is able to target dendritic cells and to deliver CD4+ or CD8+ T-cell epitopes to the major histocompatibility complex class II/I molecule presentation pathways, triggering specific Th1 or cytotoxic T-lymphocyte (CTL) responses. Several CyaA harboring either the entire TB10.4 protein or various subfragments containing the TB10.4:20-28 CTL epitope were shown to induce TB10.4-specific Th1 CD4+ and CD8+ T-cell responses. However, none of the recombinant CyaA, injected in the absence of adjuvant, was able to induce protection against M. tuberculosis infection. In contrast, TB10.4 protein administered with a cocktail of strong adjuvants that triggered a strong Th1 CD4+ T-cell response induced significant protection against M. tuberculosis challenge. These results confirm the potential value of the TB10.4 protein as a candidate vaccine and show that the presence of high frequencies of CD4+ T cells specific to this strong immunogen correlates with protection against M. tuberculosis infection.

* Corresponding author. Mailing address: Biologie des Régulations Immunitaires, Inserm, E 352, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France. Phone: 01 45 68 86 18. Fax: 01 45 68 85 40. E-mail: cleclerc{at}pasteur.fr.

Editor: J. L. Flynn

{dagger} S.H.-S. and L.M. contributed equally to this work.

Infection and Immunity, June 2006, p. 3396-3407, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.02086-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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