CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.
OBJECTIVE
IL-17 secreting CD4 (Th17) and CD8 (Tc17) T cells have been implicated in immune-mediated liver diseases, but the molecular basis for their recruitment and positioning within the liver is unknown.


METHODS
The phenotype and migratory behaviour of human liver-derived Th17 and Tc17 cells were investigated by flow cytometry and chemotaxis and flow-based adhesion assays. The recruitment of murine Th17 cells to the liver was studied in vivo using intra-vital microscopy.


RESULTS
IL-17(+) T cells comprised 1-3% of the T cell infiltrate in inflammatory liver diseases and included both CD4 (Th17) and CD8 (Tc17) cells. They expressed RORC and the IL-23 receptor and included subsets that secreted IL-22 and interferon-γ. Th17 and Tc17 cells expressed high levels of CXCR3 and CCR6, Tc17 cells also expressed CXCR6. Binding to human sinusoidal endothelium from flow was dependent on β1 and β2 integrins, CXCR3, and, in the case of Th17 cells, VAP-1. Th17 recruitment via sinusoids in mice with liver inflammation was reduced by treatment with antibodies against CXCR3 ligands, confirming the role of CXCR3 in Th17 recruitment in vivo. In human liver, IL-17(+) cells were detected in portal infiltrates close to inflamed bile ducts expressing the CCR6 ligand CCL20. Cytokine-treated human cholangiocytes secreted CCL20 and induced CCR6-dependent migration of Th17 cells suggesting that local cholangiocyte chemokine secretion localises Th17 cells to bile ducts.


CONCLUSIONS
CXCR3 promotes recruitment of Th17 cells from the blood into the liver in both human and murine liver injury. Their subsequent positioning near bile ducts is dependent on cholangiocyte-secreted CCL20.
Centre for Liver Research & NIHR Biomedical Research Unit in Liver Disease, University of Birmingham, Birmingham, United Kingdom. y.h.oo@bham.ac.uk
Ye Htun
YH
Oo
Vanessa
V
Banz
Dean
D
Kavanagh
Evaggelia
E
Liaskou
David R
DR
Withers
Elizabeth
E
Humphreys
Gary M
GM
Reynolds
Laura
L
Lee-Turner
Neena
N
Kalia
Stefan G
SG
Hubscher
Paul
P
Klenerman
Bertus
B
Eksteen
David H
DH
Adams
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism; D004195:Disease Models, Animal; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D054399:Receptors, CCR6 / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology*
C108355:CCL20 protein, human; C493447:CCL20 protein, mouse; C106311:CCR6 protein, human; C498126:CCR6 protein, mouse; C515187:CXCR3 protein, human; D054418:Chemokine CCL20; C515188:Cxcr3 protein, mouse; D054399:Receptors, CCR6; D054367:Receptors, CXCR3