![]() ![]() However, after Salmonella infection and systemic colonization, adoptively transferred FliC-specific SM1-transgenic CD4 + T cells proliferate in the PPs, but not in the spleen ( 34), suggesting that FliC-specific CD4 + T cells may only provide protection in select compartments in vivo. FliC is one important Ag recognized by B and T cells from previously infected mice and humans ( 30, 31) and is a protective Ag after immunization ( 32, 33). It is unclear what other advantages these modifications may have for bacterial survival and/or evasion.Īdaptive immunity to Salmonella infection relies not only on B cells ( 27, 28) but also on CD4 + T cells and the production of IFN-γ in vivo mice lacking CD4 + T cells or those that fail to make IFN-γ do not survive challenge with avirulent Salmonella ( 29). ST IN bacteria also modify the proteins of the outer membrane through increased expression of Mig14, VirK, and PgtE that render ST IN bacteria more resistant to CAMPs ( 19, 20). These modifications reduce the inflammatory properties of lipid A (LPS) and increase ST IN bacteria resistance to CAMPs and bile salts ( 8, 16). The most studied ST IN outer membrane modifications occur in the LPS and include decreased O-Ag length ( 17), increased acylation of lipid A to a hepta-acylated form (PhoP-dependent) ( 18), and additions of aminoarabinose and phosphoethanolamine (PmrA dependent) ( 8, 13), and 2-hydroxymyristate (PhoP dependent) ( 17). ST IN bacteria specifically modify the bacterial membrane to promote survival ( 16). Wild-type (WT) bacteria grown in conditions simulating a eukaryotic phagosome (8 μM Mg 2+) ( 4, 15) or mutant bacteria expressing excess PhoP (a global regulator of genes expressed in the phagosome) ( 6) in its active phosphorylated state (PhoP c) are models of intracellular-phase Salmonella (ST IN). Salmonellae modify the expression of >40 genes, such as slyA ( 12) and genes controlled by the PmrA/PmrB and PhoP/PhoQ regulatory systems ( 4, 13), to promote intracellular bacterial survival in the phagosome ( 14). The transition to an intracellular phase is a key bacterial virulence mechanism and is required for Salmonella survival in the host bacteria unable to survive in phagocytes are avirulent in vivo ( 6). Together, these mechanisms may restrain DC-mediated activation of FliC-specific CD4 + T cells. These data indicate that ST IN bacteria restrict FliC bioavailability by Ag compartmentalization, and together with ST IN bacterial responses, limit DC maturation and cytokine production. Furthermore, ST IN bacteria, unlike ST EX, limited DC activation as measured by increased MHC class II, CD86, TNF-α, and IL-12 expression. ![]() The combination of ST IN-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. ![]() ![]() However, ST IN bacteria, except when lysed, expressed FliC within a protected intracellular compartment and evaded stimulation of FliC-specific T cells. FliC expressed by ST EX bacteria was efficiently presented by splenic APCs to FliC-specific CD4 + T cells in vitro. Approximately 50% of the Salmonella-specific CD4 + T cells from Salmonella-immune mice were FliC specific and produced IFN-γ, demonstrating the potent immunogenicity of FliC. In this study, we tested the hypothesis that changes in FliC compartmentalization and bacterial responses triggered during the transition from ST EX to ST IN combine to reduce the ability of APCs to present FliC to CD4 + T cells. Previously, we demonstrated that systemic ST IN bacteria repress FliC below the activation threshold of FliC-specific T cells. During infection, Salmonella transitions from an extracellular-phase (ST EX, growth outside host cells) to an intracellular-phase (ST IN, 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. ![]()
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