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Attenuated Yersinia pseudotuberculosis Carrier Vaccine for Simultaneous Antigen-Specific CD4 and CD8 T-Cell Induction

Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig Maximilians Universität München, 80336 Munich,¹ Institut für Medizinische Mikrobiologie und Hygiene, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, 68167 Mannheim, Germany,³ Department of Molecular Biology, University of Umeå, 90187 Umeå, Sweden²

Received 21 January 2003/ Returned for modification 17 March 2003/ Accepted 21 March 2003

Yersinia pseudotuberculosis employs a type III secretion system for targeting of several virulence factors directly to the cytosol of eukaryotic cells. This protein translocation mechanism mediates the ability of Yersinia to resist phagocytosis and is required for sustained extracellular bacterial replication. In the present study, the Yersinia outer protein E (YopE) was used as a carrier molecule for type III-dependent secretion and translocation of listeriolysin O (LLO) from Listeria monocytogenes. In comparison to wild-type Yersinia, an attenuated Y. pseudotuberculosis yopK-null mutant strain hypertranslocates chimeric YopE/LLO into the cytosol of macrophages, resulting in enhanced major histocompatibility complex (MHC) class I-restricted antigen presentation of an LLO-derived CD8 T-cell epitope. Remarkably, T-cell activation assays also revealed a superior ability of translocated over secreted LLO to induce MHC class II-restricted antigen presentation. These in vitro observations were confirmed after immunization of mice with a single dose of the yopK-null mutant strain. Animals orally inoculated with recombinant Yersinia expressing translocated chimeric YopE/LLO revealed high numbers of gamma interferon-producing LLO-specific CD4 and CD8 T cells. For the first time, it is shown that cytosolic antigen display mediated by an extracellular bacterial carrier vaccine results in simultaneous CD4 and CD8 T-cell priming, conferring protection against an intracellular pathogen.

Editor: J. T. Barbieri

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