Abstract
Mucosal tissues require constant immune surveillance to clear harmful pathogens while maintaining tolerance to self Ags. Regulatory T cells (Tregs) play a central role in this process and expression of alpha(E)beta(7) has been reported to define a subset of Tregs with tropism for inflamed tissues. However, the signals responsible for recruiting Tregs to epithelial surfaces are poorly understood. We have isolated a subset of CCR10-expressing CD25+CD4+Foxp3+ Tregs with potent anti-inflammatory properties from chronically inflamed human liver. The CCR10+ Tregs were detected around bile ducts that expressed increased levels of the CCR10 ligand CCL28. CCL28 was secreted by primary human cholangiocytes in vitro in response to LPS, IL-1beta, or bile acids. Exposure of CCR10+ Tregs to CCL28 in vitro stimulated migration and adhesion to mucosal addressin cell adhesion molecule-1 and VCAM-1. Liver-derived CCR10+ Tregs expressed low levels of CCR7 but high levels of CXCR3, a chemokine receptor associated with infiltration into inflamed tissue and contained a subset of alpha(E)beta7(+) cells. We propose that CXCR3 promotes the recruitment of Tregs to inflamed tissues and CCR10 allows them to respond to CCL28 secreted by epithelial cells resulting in the accumulation of CCR10+ Tregs at mucosal surfaces.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bile Ducts / immunology
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Bile Ducts / metabolism
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Bile Ducts / pathology*
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Cells, Cultured
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Chemokines / biosynthesis*
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Chemokines / metabolism
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Chemokines, CC
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Chemotaxis, Leukocyte / immunology*
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Cholangitis, Sclerosing / immunology
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Cholangitis, Sclerosing / metabolism
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Cholangitis, Sclerosing / pathology
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Chronic Disease
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Epithelial Cells / immunology*
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Epithelial Cells / metabolism
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Epithelial Cells / pathology*
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Forkhead Transcription Factors / biosynthesis
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Humans
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Immunity, Mucosal
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology*
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Interleukin-1 / pharmacology
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Interleukin-10 / biosynthesis
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Interleukin-10 / metabolism
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Lipopolysaccharides / pharmacology
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Liver Cirrhosis, Biliary / immunology
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Liver Cirrhosis, Biliary / metabolism
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Liver Cirrhosis, Biliary / pathology
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Liver Diseases, Alcoholic / immunology
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Liver Diseases, Alcoholic / metabolism
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Liver Diseases, Alcoholic / pathology
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Receptors, CCR10
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Receptors, CCR7
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Receptors, CXCR3
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Receptors, Chemokine / biosynthesis*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / pathology*
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Up-Regulation / immunology
Substances
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CCL28 protein, human
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CCR10 protein, human
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CCR7 protein, human
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CXCR3 protein, human
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Chemokines
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Chemokines, CC
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FOXP3 protein, human
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Forkhead Transcription Factors
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Inflammation Mediators
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Interleukin-1
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Lipopolysaccharides
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Receptors, CCR10
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Receptors, CCR7
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Receptors, CXCR3
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Receptors, Chemokine
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Interleukin-10