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Departments of
* Laboratory Medicine and
Microbiology, University of Washington, Seattle, WA 98195
During infection, Salmonella transitions from an extracellular-phase (STEX, growth outside host cells) to an intracellular-phase (STIN, growth inside host cells): changes in gene expression mediate survival in the phagosome and modifies LPS and outer membrane protein expression, including altered production of FliC, an Ag recognized by immune CD4+ T cells. Previously, we demonstrated that systemic STIN bacteria repress FliC below the activation threshold of FliC-specific T cells. In this study, we tested the hypothesis that changes in FliC compartmentalization and bacterial responses triggered during the transition from STEX to STIN combine to reduce the ability of APCs to present FliC to CD4+ T cells. Approximately 50% of the Salmonella-specific CD4+ T cells from Salmonella-immune mice were FliC specific and produced IFN-
, demonstrating the potent immunogenicity of FliC. FliC expressed by STEX bacteria was efficiently presented by splenic APCs to FliC-specific CD4+ T cells in vitro. However, STIN bacteria, except when lysed, expressed FliC within a protected intracellular compartment and evaded stimulation of FliC-specific T cells. The combination of STIN-mediated responses that reduced FliC bioavailability were overcome by dendritic cells (DCs), which presented intracellular FliC within heat-killed bacteria; however, this ability was abrogated by live bacterial infection. Furthermore, STIN bacteria, unlike STEX, limited DC activation as measured by increased MHC class II, CD86, TNF-
, and IL-12 expression. These data indicate that STIN bacteria restrict FliC bioavailability by Ag compartmentalization, and together with STIN bacterial responses, limit DC maturation and cytokine production. Together, these mechanisms may restrain DC-mediated activation of FliC-specific CD4+ T cells.
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 National Institutes of Health Grant AI47242.
2 Current address: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02112.
3 Address correspondence and reprint requests to: Dr. Brad T. Cookson, Department of Laboratory Medicine and Microbiology, University of Washington Medical Center, Box 357110, 1959 Northeast Pacific Street, Seattle, WA 98195. E-mail address: cookson{at}u.washington.edu
4 Abbreviations used in this paper: PP, Peyer’s patch; CAMP, cationic antimicrobial peptide; STIN, intracellular-phase Salmonella; STEX, extracellular-phase Salmonella; DC, dendritic cell; ICS, intracellular cytokine staining; MHC class II, MHC-II; MOI, multiplicity of infection; SPI-2, Salmonella-pathogenicity island 2.
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