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.
Highlights
Th17 are a distinct subset of CD4 effector cells [1,2] that develop under control of the nuclear receptor RORc in humans (RORct in mice) [3,4], in response to antigen priming in an environment rich in IL-6 and TGF-b [5,6]
Immunohistochemistry revealed that the normal human liver contained very few IL-17 cells (Fig. 1B and G) whereas numbers of intra-hepatic IL-17+ cells increased in all chronic liver diseases studied (Fig. 1C–F, and G)
IL-17+ cells comprised around 2–3% of the CD3 T cell infiltrate in liver disease, as defined by frequencies generated by immunohistochemical analysis (Fig. 1G) and by calculating the frequencies of CD3+ IL-17 secreting cells, in cells freshly isolated from liver tissue by flow cytometry (Fig. 1H)
Summary
Th17 are a distinct subset of CD4 effector cells [1,2] that develop under control of the nuclear receptor RORc in humans (RORct in mice) [3,4], in response to antigen priming in an environment rich in IL-6 and TGF-b [5,6]. Stimulation with IL-6, IL-21 or IL-1b and TGF-b increases expression of the IL-23 receptor [9] through which IL-23 stabilises the Th17 phenotype [2,9,10] Both Th1 and Th17 cells have been implicated in inflammation and autoimmunity [11] and IL-23 shares the p40 subunit with the classical Th1 cytokine IL-12 [12]. We have recently reported high frequencies of Tc17 in human HCV-infected livers that correlate with control of disease progression [22]. Both Th17 and Tc17 are detected in chronic hepatitis, little is known about the molecular basis of their recruitment and subsequent positioning within the liver. We show that CXCR3 is critical for Th17 recruitment from the blood into the inflamed liver and that CCR6 is involved in subsequent positioning at epithelial interfaces
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