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1.
Immunity ; 24(5): 623-32, 2006 May.
Article in English | MEDLINE | ID: mdl-16713979

ABSTRACT

T cell activation by dendritic cells (DCs) is critical to the initiation of adaptive immune responses and protection against pathogens. Here, we demonstrate that a specialized DC subset in Peyer's patches (PPs) mediates the rapid activation of pathogen specific T cells. This DC subset is characterized by the expression of the chemokine receptor CCR6 and is found only in PPs. CCR6(+) DCs were recruited into the dome regions of PPs upon invasion of the follicle associated epithelium (FAE) by an enteric pathogen and were responsible for the rapid local activation of pathogen-specific T cells. CCR6-deficient DCs were unable to respond to bacterial invasion of PPs and failed to initiate T cell activation, resulting in reduced defense against oral infection. Thus, CCR6-dependent regulation of DCs is responsible for localized T cell dependent defense against entero-invasive pathogens.


Subject(s)
Dendritic Cells/immunology , Lymphocyte Activation/immunology , Peyer's Patches/immunology , Receptors, Chemokine/immunology , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Dendritic Cells/metabolism , Flow Cytometry , Image Processing, Computer-Assisted , Immunity, Mucosal/physiology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal , Peyer's Patches/cytology , Peyer's Patches/microbiology , Receptors, CCR6 , Receptors, Chemokine/metabolism , Salmonella Infections/immunology , Salmonella typhimurium/immunology , T-Lymphocytes/metabolism
2.
Science ; 307(5707): 254-8, 2005 Jan 14.
Article in English | MEDLINE | ID: mdl-15653504

ABSTRACT

Dendritic cells (DCs) and macrophages are critical to innate and adaptive immunity to the intestinal bacterial microbiota. Here, we identify a myeloid-derived mucosal DC in mice, which populates the entire lamina propria of the small intestine. Lamina propria DCs were found to depend on the chemokine receptor CX3CR1 to form transepithelial dendrites, which enable the cells to directly sample luminal antigens. CX3CR1 was also found to control the clearance of entero-invasive pathogens by DCs. Thus, CX3CR1-dependent processes, which control host interactions of specialized DCs with commensal and pathogenic bacteria, may regulate immunological tolerance and inflammation.


Subject(s)
Dendritic Cells/immunology , Escherichia coli/immunology , Immunity, Mucosal , Intestinal Mucosa/immunology , Receptors, Chemokine/physiology , Salmonella Infections, Animal/immunology , Salmonella typhimurium/immunology , Animals , CX3C Chemokine Receptor 1 , Chemokine CX3CL1 , Chemokines, CX3C/metabolism , Dendritic Cells/cytology , Dendritic Cells/microbiology , Escherichia coli/isolation & purification , Gene Deletion , Green Fluorescent Proteins/metabolism , Ileum/cytology , Ileum/immunology , Intestinal Mucosa/microbiology , Intestine, Small/immunology , Intestine, Small/microbiology , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Peyer's Patches/immunology , Peyer's Patches/microbiology , Phagocytosis , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Salmonella Infections, Animal/microbiology , Salmonella typhimurium/isolation & purification
3.
Cell Microbiol ; 4(6): 367-81, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12067320

ABSTRACT

Shigella spp. are a group of Gram-negative enteric bacilli that cause acute dysentery in humans. We demonstrate that Shigella flexneri has evolved the ability to regulate functional components of tight junctions after interaction at the apical and basolateral pole of model intestinal epithelia. In the regulation of tight junctional protein assemblies, S. flexneri can engage serotype-specific mechanisms, which targets not only expression, but also cellular distribution and membrane association of components of tight junctions. Distinct mechanisms resulting in the regulation of tight junction-associated proteins are initiated after either apical or basolateral interactions. S. flexneri serotype 2a has the ability to remove claudin-1 from Triton X-insoluble protein fractions upon apical exposure to T-84 cell monolayers. S. flexneri serotype 2a and 5, but not the non-invasive Escherichia coli strain F-18, share the ability to regulate expression of ZO-1, ZO-2, E-cadherin and to dephosphorylate occludin. The disruption of tight junctions is dependent on direct interaction of living Shigella with intestinal epithelial cells and is supported by heat-stable secreted bacterial products. Intestinal epithelial cells have the ability to compensate in part for S. flexneri induced regulation of tight junction-associated proteins.


Subject(s)
Intestinal Mucosa/metabolism , Membrane Proteins/metabolism , Shigella flexneri/physiology , Tight Junctions/metabolism , Cadherins/metabolism , Cell Polarity/physiology , Claudin-1 , Down-Regulation , Humans , Intestinal Mucosa/cytology , Occludin , Phosphoproteins/metabolism , Proteins/physiology , Shigella flexneri/classification , Species Specificity , Zonula Occludens-1 Protein , Zonula Occludens-2 Protein
4.
J Biol Chem ; 277(24): 21361-70, 2002 Jun 14.
Article in English | MEDLINE | ID: mdl-11934881

ABSTRACT

Claudin-2 is a structural component of tight junctions in the kidneys, liver, and intestine, but the mechanisms regulating its expression have not been defined. The 5'-flanking region of the claudin-2 gene contains binding sites for intestine-specific Cdx homeodomain proteins and hepatocyte nuclear factor (HNF)-1, which are conserved in human and mouse. Both Cdx1 and Cdx2 activated the claudin-2 promoter in the human intestinal epithelial cell line Caco-2. HNF-1alpha augmented the Cdx2-induced but not Cdx1-induced transcriptional activation of the human claudin-2 promoter. In mice, HNF-1alpha was required for claudin-2 expression in the villus epithelium of the ileum and within the liver but not in the kidneys, indicating an organ-specific function of HNF-1alpha in the regulation of claudin-2 gene expression. Tight junction structural components, which determine epithelial polarization and intestinal barrier function, can be regulated by homeodomain proteins that control the differentiation of the intestinal epithelium.


Subject(s)
DNA-Binding Proteins , Gene Expression Regulation, Neoplastic , Membrane Proteins/genetics , Membrane Proteins/physiology , Nuclear Proteins , Promoter Regions, Genetic , Transcription Factors/metabolism , 3T3 Cells , Animals , Base Sequence , Binding Sites , Blotting, Northern , Blotting, Western , CDX2 Transcription Factor , Caco-2 Cells , Cell Nucleus/metabolism , Claudins , Cloning, Molecular , DNA Mutational Analysis , Epithelial Cells/metabolism , Gene Deletion , Genes, Reporter , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Homeodomain Proteins/metabolism , Humans , Ileum/metabolism , Intestinal Mucosa/metabolism , Liver/metabolism , Luciferases/metabolism , Mice , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Binding , Protein Structure, Tertiary , RNA/metabolism , Tissue Distribution , Trans-Activators , Transcriptional Activation , Transfection
5.
Gastroenterology ; 122(1): 166-77, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11781291

ABSTRACT

BACKGROUND & AIMS: In this study, we determined the signal transduction and functional consequences after ligand-specific activation of the fractalkine receptor CX3CR1 in human intestinal epithelial cells. METHODS: CX3CR1 expression in human colonic tissues and intestinal epithelial cell lines was determined by immunohistochemistry, immunoblotting, and reverse-transcription polymerase chain reaction. The regulation of mitogen-activated protein kinase (MAPK) activation was assessed by immunoblotting. Regulation of chemokine messenger RNA (mRNA) expression was determined by Northern blotting. NF-kappa B and p53 activation was assessed by electromobility shift assays. RESULTS: Fractalkine mediated the MEK-1 and G alpha i-dependent but phosphatidylinositol-3-kinase-independent activation of extracellular signal-regulated kinase-MAPK. Fractalkine activated NF-kappa B and p53 resulting in interleukin 8 and fractalkine mRNA expression. CX3CR1-mediated activation of intestinal epithelial cells was able to induce migration of human neutrophils into but not through the intestinal epithelial cell monolayer. CONCLUSIONS: CX3CR1 mediates distinct functional responses in intestinal epithelial cells, which include the autocrine regulation of cell-survival signals and activation of immune modulators, indicating a role of CX3CR1 in host defense mechanisms originating from the intestinal epithelium.


Subject(s)
Adjuvants, Immunologic/metabolism , Intestinal Mucosa/metabolism , MAP Kinase Signaling System/immunology , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism , Receptors, HIV/genetics , Receptors, HIV/metabolism , Autocrine Communication/immunology , CX3C Chemokine Receptor 1 , Caco-2 Cells , Cell Division/physiology , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cell Survival/physiology , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Gene Expression/physiology , Humans , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , MAP Kinase Kinase 1 , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Neutrophils/cytology , Phosphatidylinositol 3-Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Receptors, Cytokine/immunology , Receptors, HIV/immunology , Stomach Neoplasms , Tumor Suppressor Protein p53/metabolism
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