Research ArticleIntrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis C

Background & AimsRegulatory CD4+ T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions.MethodsUsing microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C.ResultsWe found substantial upregulation of IL-8 in Foxp3+CD4+ Tregs from chronic hepatitis C. Activated GARP-positive IL-8+ Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody.ConclusionsOur studies identified Foxp3+CD4+ Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3+CD4+ Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.