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DOI: 10.1055/s-0032-1331898
Hepatic accumulation of IL-17 producing γδ T cells via chemokine receptor CCR6 restricts liver inflammation and fibrosis by inhibiting hepatic stellate cells
Aim: The chemokine receptor CCR6 is known to be expressed on some T helper cells and γδ T cells, monocyte derived dendritic cells and B cell subsets. It plays an important role in mucosal immunity, but its role in liver disease is largely unknown. In this study we investigated its functional relevance in chronic liver disease and hepatic fibrosis.
Methods: Liver inflammation and fibrosis was induced in wildtype (wt) and Ccr6-/- mice by carbon tetrachloride (CCl4) thrice weekly over 4 weeks. Immune cell subsets were isolated from livers by FACS sorting and co-cultured with stellate cells. Human liver samples from patients with chronic liver disease (n=50) were analysed by qPCR.
Results: CCR6 and its ligand CCL20 are strongly upregulated upon chronic liver injury in mice and in human patients with cirrhosis. Ccr6-/- mice develop more severe hepatic fibrosis compared to wt mice when treated with CCl4. They also show strongly enhanced liver inflammation compared to wt mice, as indicated by increased overall infiltration of immune cells to the liver. We could not detect changes in infiltrating macrophages or composition of T helper cell subtypes between wt and Ccr6-deficient mice, but expression of interleukin-17 (IL-17) was significantly reduced in livers of Ccr6-/- mice. While wt mice showed an accumulation of IL-17-producing γδ T cells in the liver upon CCl4 treatment, this cell type was markedly reduced in livers of Ccr6-/- mice. The adoptive transfer of wt γδ T cells, but not CD4 T cells, into Ccr6-/- mice restored hepatic inflammation and fibrosis in the chronic injury model. Suprisingly, this effect was independent of their IL-17 production, as transfer of IL-17-deficient γδ T cells into Ccr6-/- mice also reduced hepatic fibrosis. In co-culture experiments, hepatic γδ T cells directly inhibited hepatic stellate cells (HSC) by limiting their collagen synthesis and facilitating HSC apoptosis.
Conclusions: Thus, IL-17 producing γδ T cells specifically require CCR6 to accumulate in the liver upon chronic injury and protect the liver from excessive inflammation and fibrosis by inhibiting HSC.