Chemokine Receptor CCR6-dependent Accumulation of γδ T Cells in Injured Liver Restricts Hepatic Inflammation and Fibrosis

Hepatology. 2014 Feb;59(2):630-42. doi: 10.1002/hep.26697. Epub 2013 Dec 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Case-Control Studies
  • Cell Movement*
  • Chemokine CCL20 / metabolism
  • Disease Models, Animal
  • Female
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Hepatitis / prevention & control*
  • Humans
  • Interleukin-17 / metabolism
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / prevention & control*
  • Liver Diseases / metabolism*
  • Liver Diseases / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Receptors, CCR6 / deficiency
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / metabolism*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / metabolism
  • Th17 Cells / pathology
  • Up-Regulation

Substances

  • CCR6 protein, human
  • Chemokine CCL20
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, CCR6