Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.
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.
Eksteen
Bertus
B
Liver Research Laboratories, Medical Research Council for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TH, UK.
Miles
Alice
A
Curbishley
Stuart M
SM
Tselepis
Chris
C
Grant
Allister J
AJ
Walker
Lucy S K
LS
Adams
David H
DH
D001652:Bile Ducts / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000378:metabolism; D019742:Chemokines, CC; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D015209:Cholangitis, Sclerosing / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054447:Receptors, CCR10; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000276:immunology
C414047:CCL28 protein, human; C515706:CCR10 protein, human; C515370:CCR7 protein, human; C515187:CXCR3 protein, human; D018925:Chemokines; D019742:Chemokines, CC; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D054447:Receptors, CCR10; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D016753:Interleukin-10