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Inhibition of Phagosome Maturation by Mycobacteria Does Not Interfere with Presentation of Mycobacterial Antigens by MHC Molecules¹

Laleh Majlessi^2,3,*,, Benoit Combaluzier^3,, Imke Albrecht, Jessica E. Garcia^*,, Clémence Nouze^*,, Jean Pieters and Claude Leclerc^*,

^* Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 883, Paris, France; and Biozentrum, University of Basel, Klingelbergstrasse 50, Basel, Switzerland

Pathogenic mycobacteria escape host innate immune responses by surviving within phagosomes of host macrophages and blocking their delivery to lysosomes. Avoiding lysosomal delivery may also be involved in the capacity of living mycobacteria to modulate MHC class I- or II-dependent T cell responses, which may contribute to their pathogenicity in vivo. In this study, we show that the presentation of mycobacterial Ags is independent of the site of intracellular residence inside professional APCs. Infection of mouse macrophages or dendritic cells in vitro with mycobacterial mutants that are unable to escape lysosomal transfer resulted in an identical efficiency of Ag presentation compared with wild-type mycobacteria. Moreover, in vivo, such mutants induced CD4⁺ Th1 or CD8⁺ CTL responses in mice against various mycobacterial Ags that were comparable to those induced by their wild-type counterparts. These results suggest that the limiting factor for the generation of an adaptive immune response against mycobacteria is not the degree of lysosomal delivery. These findings are important in the rational design of improved vaccines to combat mycobacterial diseases.

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 grants from the Institut Pasteur (Programme Transversal de Recherche 110, to L.M.), the European Community (Cellprom, to C.L.), the Swiss National Science Foundation the Swiss Life Jubileum Fund, and the World Health Organization (to J.P.).

² Address correspondence and reprint requests to Dr. Laleh Majlessi, Régulation Immunitaire et Vaccinologie, Institut National de la Santé et de la Recherche Médicale, Unité 883, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, Cedex 15, France. E-mail address: lmajless{at}pasteur.fr

³ L.M. and B.C. contributed equally to this work.

⁴ Abbreviations used in this paper: MHC-II,I. MHC class II/I; BCG, bacillus Calmette-Guérin; LAMP, lysosome-associated membrane protein; PknG, protein kinase G; Ii, invariant chain; BM, bone marrow; PPD, purified protein derivative; ESAT-6, early secreted antigenic target-6-kDa.

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