Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis
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Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis. / Hammerich, Linda; Bangen, Jörg M; Govaere, Olivier; Zimmermann, Henning W; Gassler, Nikolaus; Huss, Sebastian; Liedtke, Christian; Prinz, Immo; Lira, Sergio A; Luedde, Tom; Roskams, Tania; Trautwein, Christian; Heymann, Felix; Tacke, Frank.
in: HEPATOLOGY, Jahrgang 59, Nr. 2, 02.2014, S. 630-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis
AU - Hammerich, Linda
AU - Bangen, Jörg M
AU - Govaere, Olivier
AU - Zimmermann, Henning W
AU - Gassler, Nikolaus
AU - Huss, Sebastian
AU - Liedtke, Christian
AU - Prinz, Immo
AU - Lira, Sergio A
AU - Luedde, Tom
AU - Roskams, Tania
AU - Trautwein, Christian
AU - Heymann, Felix
AU - Tacke, Frank
N1 - © 2013 by the American Association for the Study of Liver Diseases.
PY - 2014/2
Y1 - 2014/2
N2 - UNLABELLED: Chronic liver injury promotes hepatic inflammation, representing a prerequisite for organ fibrosis. We hypothesized a contribution of chemokine receptor CCR6 and its ligand, CCL20, which may regulate migration of T-helper (Th)17, regulatory, and gamma-delta (γδ) T cells. CCR6 and CCL20 expression was intrahepatically up-regulated in patients with chronic liver diseases (n = 50), compared to control liver (n = 5). Immunohistochemistry revealed the periportal accumulation of CCR6(+) mononuclear cells and CCL20 induction by hepatic parenchymal cells in liver disease patients. Similarly, in murine livers, CCR6 was expressed by macrophages, CD4 and γδ T-cells, and up-regulated in fibrosis, whereas primary hepatocytes induced CCL20 upon experimental injury. In two murine models of chronic liver injury (CCl4 and methionine-choline-deficient diet), Ccr6(-/-) mice developed more severe fibrosis with strongly enhanced hepatic immune cell infiltration, compared to wild-type (WT) mice. Although CCR6 did not affect hepatic Th-cell subtype composition, CCR6 was explicitly required by the subset of interleukin (IL)-17- and IL-22-expressing γδ T cells for accumulation in injured liver. The adoptive transfer of WT γδ, but not CD4 T cells, into Ccr6(-/-) mice reduced hepatic inflammation and fibrosis in chronic injury to WT level. The anti-inflammatory function of hepatic γδ T cells was independent of IL-17, as evidenced by transfer of Il-17(-/-) cells. Instead, hepatic γδ T cells colocalized with hepatic stellate cells (HSCs) in vivo and promoted apoptosis of primary murine HSCs in a cell-cell contact-dependent manner, involving Fas-ligand (CD95L). Consistent with γδ T-cell-induced HSC apoptosis, activated myofibroblasts were more frequent in fibrotic livers of Ccr6(-/-) than in WT mice.CONCLUSION: γδ T cells are recruited to the liver by CCR6 upon chronic injury and protect the liver from excessive inflammation and fibrosis by inhibiting HSCs.
AB - UNLABELLED: Chronic liver injury promotes hepatic inflammation, representing a prerequisite for organ fibrosis. We hypothesized a contribution of chemokine receptor CCR6 and its ligand, CCL20, which may regulate migration of T-helper (Th)17, regulatory, and gamma-delta (γδ) T cells. CCR6 and CCL20 expression was intrahepatically up-regulated in patients with chronic liver diseases (n = 50), compared to control liver (n = 5). Immunohistochemistry revealed the periportal accumulation of CCR6(+) mononuclear cells and CCL20 induction by hepatic parenchymal cells in liver disease patients. Similarly, in murine livers, CCR6 was expressed by macrophages, CD4 and γδ T-cells, and up-regulated in fibrosis, whereas primary hepatocytes induced CCL20 upon experimental injury. In two murine models of chronic liver injury (CCl4 and methionine-choline-deficient diet), Ccr6(-/-) mice developed more severe fibrosis with strongly enhanced hepatic immune cell infiltration, compared to wild-type (WT) mice. Although CCR6 did not affect hepatic Th-cell subtype composition, CCR6 was explicitly required by the subset of interleukin (IL)-17- and IL-22-expressing γδ T cells for accumulation in injured liver. The adoptive transfer of WT γδ, but not CD4 T cells, into Ccr6(-/-) mice reduced hepatic inflammation and fibrosis in chronic injury to WT level. The anti-inflammatory function of hepatic γδ T cells was independent of IL-17, as evidenced by transfer of Il-17(-/-) cells. Instead, hepatic γδ T cells colocalized with hepatic stellate cells (HSCs) in vivo and promoted apoptosis of primary murine HSCs in a cell-cell contact-dependent manner, involving Fas-ligand (CD95L). Consistent with γδ T-cell-induced HSC apoptosis, activated myofibroblasts were more frequent in fibrotic livers of Ccr6(-/-) than in WT mice.CONCLUSION: γδ T cells are recruited to the liver by CCR6 upon chronic injury and protect the liver from excessive inflammation and fibrosis by inhibiting HSCs.
KW - Animals
KW - Apoptosis
KW - Case-Control Studies
KW - Cell Movement
KW - Chemokine CCL20/metabolism
KW - Disease Models, Animal
KW - Female
KW - Hepatitis/metabolism
KW - Humans
KW - Interleukin-17/metabolism
KW - Liver Cirrhosis/metabolism
KW - Liver Diseases/metabolism
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Receptors, Antigen, T-Cell, gamma-delta/metabolism
KW - Receptors, CCR6/deficiency
KW - T-Lymphocytes/metabolism
KW - T-Lymphocytes, Regulatory/metabolism
KW - Th17 Cells/metabolism
KW - Up-Regulation
U2 - 10.1002/hep.26697
DO - 10.1002/hep.26697
M3 - SCORING: Journal article
C2 - 23959575
VL - 59
SP - 630
EP - 642
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 2
ER -
