CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver

Abstract

Background & AimsIL-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.MethodsThe 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.ResultsIL-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.ConclusionsCXCR3 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.

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

“…This scenario is supported by recent data in mice showing that the expansion and differentiation of Th17 cells in the gut were controlled by an IL-17A-dependent production of CCL20 in gut mucosa (46). Indeed, we observed that Liv-MAIT cells produced both IL-17A and CCL20, supporting the possible role for MAIT cells in the liver-driven recruitment of inflammatory CCR6 + Th17 cells (27,28).…”

“…We also observed that intrahepatic MAIT cells were the T cell subset primarily able to secrete CCL20 (Fig. 5B), the known ligand of CCR6, which is expressed on Th17 (27,28) and MAIT cells (Supplemental Fig. 3).…”

CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid

“…However, Chuang et al [16] have already demonstrated their presence in the portal tract of PBC patients. Moreover, a very recent paper has demonstrated that Tregs not only express CXCR3, but also Th17 and Tc17 + lymphocytes [17]. These findings suggest that a future detailed quantitative study is necessary to clarify the situation.…”

Testosterone Suppresses Hepatic Inflammation by the Downregulation of IL-17, CXCL-9, and CXCL-10 in a Mouse Model of Experimental Acute Cholangitis

“…The proinflammatory chemokines CXCL-9-11 are involved in the recruitment of CXCR3 + , CD4 + , and CD8+ T cells and are known to be expressed by hepatocytes, cholangiocytes, and stellate cells (29,30). Furthermore, IL-17 has been demonstrated to increase the expression of chemokines, such as CXCL-9, CXCL-11, and CCL-20, by biliary epithelial cells (29)(30)(31). Therefore, it was possible that the increased IL-17 expression by female lymphocytes could feed chemokine secretion by liver cells, which in turn could lead to the recruitment of lymphocytes into portal tracts (31).…”

“…Furthermore, IL-17 has been demonstrated to increase the expression of chemokines, such as CXCL-9, CXCL-11, and CCL-20, by biliary epithelial cells (29)(30)(31). Therefore, it was possible that the increased IL-17 expression by female lymphocytes could feed chemokine secretion by liver cells, which in turn could lead to the recruitment of lymphocytes into portal tracts (31). In female livers, the expression of CXCL-9 and CXCL-10 was found to be significantly increased as compared with male livers.…”