Thomas Fabre

IL-17 producing cells, known as Th17 cells were implicated in several inflammatory conditions of the gut including liver fibrosis. In this paper, we demonstrate a potential mechanism for the role of IL-17 in enhancing liver fibrosis using an in vitro model of fibrosis through stimulation of the human hepatic stellate cell (HSC) line (LX2) and primary HSCs. We demonstrate that IL-17 alone has no direct effect on expression of the fibrogenic genes but increases their sensitivity to lower doses of… Show more

IL-17 producing cells, known as Th17 cells were implicated in several inflammatory conditions of the gut including liver fibrosis. In this paper, we demonstrate a potential mechanism for the role of IL-17 in enhancing liver fibrosis using an in vitro model of fibrosis through stimulation of the human hepatic stellate cell (HSC) line (LX2) and primary HSCs. We demonstrate that IL-17 alone has no direct effect on expression of the fibrogenic genes but increases their sensitivity to lower doses of the fibrogenic cytokine TGF-beta by upregulating and stabilizing the TGF-beta receptor on the surface of HSCs. More work examining the in vivo relevance of this observation is on going. Show less

n this study, we investigated the mechanisms underlying failure of the CD4 helper T cell response during acute hepatitis C infection. We demonstrate that this failure is primarily due to loss of IL-21-producing CD4 T cells in individuals who progress towards chronic infection. This is accompanied by exhaustion of virus-specific cytotoxic CD8 T cells through upregulation of the exhaustion markers Tim-3, PD-1 and CTLA-4, higher plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and increased… Show more

n this study, we investigated the mechanisms underlying failure of the CD4 helper T cell response during acute hepatitis C infection. We demonstrate that this failure is primarily due to loss of IL-21-producing CD4 T cells in individuals who progress towards chronic infection. This is accompanied by exhaustion of virus-specific cytotoxic CD8 T cells through upregulation of the exhaustion markers Tim-3, PD-1 and CTLA-4, higher plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and increased frequency of Gal-9 producing regulatory T cells (Tregs). In vitro supplementation with IL-21 rescued HCV-specific CD8 T cells from Gal-9 induced apoptosis. Blocking Gal-9 expression in Tregs restored IL-21 production by virus-specific CD4 helper T cells. Altogether, our results suggest that failure of CD4 T cell help during acute HCV may be partially meditated by an imbalance between IL-21-producing CD4 T cells and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway is counteracted by IL-21. Show less

Jean-François Gélinas1,*, Thomas Fabre1,2, Philippe Willems1, Reynold C. Leung3, Jacob
George3, Bernard Willems1,4, Julie Bruneau1,5 and Naglaa H. Shoukry1,4,†