title: Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
authors: Linda
authors: L
authors: Hammerich
authors: Jörg M
authors: JM
authors: Bangen
authors: Olivier
authors: O
authors: Govaere
authors: Henning W
authors: HW
authors: Zimmermann
authors: Nikolaus
authors: N
authors: Gassler
authors: Sebastian
authors: S
authors: Huss
authors: Christian
authors: C
authors: Liedtke
authors: Immo
authors: I
authors: Prinz
authors: Sergio A
authors: SA
authors: Lira
authors: Tom
authors: T
authors: Luedde
authors: Tania
authors: T
authors: Roskams
authors: Christian
authors: C
authors: Trautwein
authors: Felix
authors: F
authors: Heymann
authors: Frank
authors: F
authors: Tacke
mesh_terms: D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D002465:Cell Movement; D054418:Chemokine CCL20 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D054399:Receptors, CCR6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: C106311:CCR6 protein, human; D054418:Chemokine CCL20; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054399:Receptors, CCR6
references: Gastroenterology. 2006 Feb;130(2):435-52
references: 16472598
references: J Immunol. 2008 Dec 15;181(12):8391-401
references: 19050256
references: Eur J Immunol. 2009 Jun;39(6):1671-81
references: 19499521
references: Immunity. 2009 Aug 21;31(2):331-41
references: 19682929
references: J Immunol. 2011 Sep 1;187(5):2783-93
references: 21813772
references: Immunity. 2000 May;12(5):495-503
references: 10843382
references: J Clin Invest. 2005 Feb;115(2):209-18
references: 15690074
references: J Immunol. 2011 Nov 15;187(10):5007-14
references: 21987663
references: Hepatology. 2012 Sep;56(3):1150-9
references: 22473749
references: J Exp Med. 2013 Jun 3;210(6):1117-24
references: 23690441
references: Hepatology. 2006 Feb;43(2 Suppl 1):S54-62
references: 16447271
references: J Immunol. 1999 Dec 1;163(11):6236-43
references: 10570316
references: Immunity. 2012 Jul 27;37(1):48-59
references: 22770884
references: J Hepatol. 2012 Nov;57(5):1044-51
references: 22796894
references: Hepatology. 2001 Aug;34(2):311-9
references: 11481616
references: Immunity. 2009 Aug 21;31(2):321-30
references: 19682928
references: J Am Soc Nephrol. 2012 Sep;23(9):1486-95
references: 22797181
references: Gastroenterology. 2009 Jul;137(1):309-19, 319.e1-3
references: 19344719
references: Hepatology. 2010 Nov;52(5):1769-82
references: 21038415
references: Gastroenterology. 2012 Sep;143(3):765-776.e3
references: 22687286
references: Hepatology. 2013 Jan;57(1):373-84
references: 22821628
references: J Am Soc Nephrol. 2010 Jun;21(6):974-85
references: 20299360
references: Inflamm Allergy Drug Targets. 2011 Dec;10(6):509-36
references: 22150762
references: J Clin Invest. 2005 Nov;115(11):3072-82
references: 16276416
references: Gut. 2012 Mar;61(3):416-26
references: 21813474
references: Eur J Immunol. 2009 Dec;39(12):3488-97
references: 19830744
references: Clin Dev Immunol. 2011;2011:345803
references: 21197451
references: PLoS One. 2010 Jun 10;5(6):e11049
references: 20548789
references: Gastroenterology. 2003 Oct;125(4):1060-76
references: 14517790