HCV+ Hepatocytes Induce Human Regulatory CD4+ T Cells through the Production of TGF-β

Abstract

BackgroundHepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4+ regulatory T cells (Tregs) act by dampening antiviral T cell responses in HCV infection. The mechanism for induction and/or expansion of Tregs in HCV is unknown.Methodology/Principal FindingsHCV-expressing hepatocytes were used to determine if hepatocytes are able to induce Tregs. The infected liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4+ T cells. The production of IFN-γ was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4+ T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. Importantly, HCV+ hepatocytes upregulated the production of TGF-β and blockade of TGF-β abrogated Treg phenotype and function.Conclusions/SignificanceThese results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.

Seoul Virus-Infected Rat Lung Endothelial Cells and Alveolar Macrophages Differ in Their Ability To Support Virus Replication and Induce Regulatory T Cell Phenotypes

“…ϩ T cells to preferentially differentiate into Treg cells, which contribute to the maintenance of chronic HCV infection (26). Both macrophages and endothelial cells are capable of inducing naïve CD4 ϩ T cells to differentiate into Treg cells (1,38,41,72).…”

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

“…Infection with viral pathogens, associated with increased TGF-b production, for example hepatitis C virus, leads to Treg induction and impaired protective host immune responses. 40 In addition, IL-7 has been shown to expand antigen-specific IL-17-producing T cells in a murine experimental autoimmune encephalomyelitis model. 41 We show in the current report detection of increased IL-17 production in rBCG-vaccinated NHPs when compared with BCG-vaccinated or control animals.…”

Modulation of CD4+ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis

“…Indeed, impaired CD4 + T cell responses have been associated with a higher rate of chronic disease and persistent viraemia [4,5]. The finding that hepatocytes are the primary site of HCV viral replication has led to the study of the role of liver HCV-specific T cell responses [4,6]. However, there are relatively few studies on the immune profile of human splenocytes and, even though the spleen has an important role in the induction and regulation of immune responses, the phenotypic and functional aspects of splenic CD4 + T cells in patients with HCV are, to a large extent, unknown.…”