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* Veterans Affairs Medical Center,
Earle A. Chiles Research Institute,
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239;
Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60612;
¶ Seattle Biomedical Research Institute,
|| Departments of Pathobiology and Microbiology, University of Washington, Seattle, WA 98195; and
# Department of Molecular Genetics and Microbiology, Harvard Medical School, Boston, MA 02115
The intracytosolic niche for replication of Listeria monocytogenes (Lm) facilitates delivery of bacteria-derived Ags into the MHC class I pathway for subsequent stimulation of CD8 effector T cells. Using Lm strains that are equivalent for in vivo virulence yet express marked differences in the level of secretion of a protective target Ag, we have evaluated how these specific differences in secretion levels influences the magnitude and effector function of Ag-specific CD8 T cell responses following Lm injection. Immunization with low doses of a hyperantigen-secreting Lm strain stimulated enhanced target-Ag specific CD8 T cell responses compared with the magnitude stimulated following immunization with the same dose of wild-type Lm. The enhanced determinant-specific response was also evident by in vivo CTL activity, increased numbers of memory cells 4 wk following immunization, and enhanced antilisterial protection following a challenge infection. Initiation of antibiotic treatment 24 h following infection with wild-type Lm markedly reduced the magnitude of the effector CD8 T cell response. In contrast, antibiotic treatment initiated 24 h following immunization with the hyperantigen secreting strain of Lm did not impact the frequency of the target-Ag specific CD8 T cells. Thus, immunization with a low dose of a hyperantigen secreting Lm strain, followed by antibiotic treatment to limit the extent of the infection, may represent a safe strategy for the stimulation of enhanced effector CD8 T cell responses to specific Ag by a rLm vaccine.
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 grant funds from the Veterans Affairs Merit Review program and by National Institutes of Health Grants AI56446, AI44376 (to H.G.A.B.), AI41816, AI55651 (to N.E.F.), and AI56446 (to D.E.H.).
2 Address correspondence and reprint requests to Dr. H. G. Archie Bouwer, Immunology Research RD41, Veterans Affairs Medical Center, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239. E-mail address: bouwera{at}ohsu.edu
3 Abbreviations used in this paper: Lm, Listeria monocytogenes; LLO, listeriolysin O; WT, wild type; ICS, intracellular cytokine staining.
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  P. Lauer, B. Hanson, E. E. Lemmens, W. Liu, W. S. Luckett, M. L. Leong, H. E. Allen, J. Skoble, K. S. Bahjat, N. E. Freitag, et al. Constitutive Activation of the PrfA Regulon Enhances the Potency of Vaccines Based on Live-Attenuated and Killed but Metabolically Active Listeria monocytogenes Strains Infect. Immun., August 1, 2008; 76(8): 3742 - 3753. [Abstract] [Full Text] [PDF]
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