Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C

Abstract

Hepatitis C virus, a small single-stranded RNA virus, is a major cause of chronic liver disease. Resolution of primary hepatitis C virus infections depends upon the vigorous responses of CD4(+) and CD8(+) T cells to multiple viral epitopes. Although such broad CD4(+) and CD8(+) T-cell responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Purportedly, a variety of factors contribute to the diminished T-cell responses observed in chronic, virus-infected patients including the induction of and biological suppression by CD4(+)FoxP3(+) regulatory T cells. Indeed, a wealth of evidence suggests that regulatory T cells play diverse roles in the pathogenesis of chronic hepatitis C, impairing the effector T-cell response and viral clearance early during the course of infection and suppressing liver injury as the disease progresses. The factors that affect the generation and biological response of regulatory T cells in chronic, hepatitis C virus-infected patients is discussed.

Keywords: dendritic cells; hepatitis C; immune tolerance; liver disease; regulatory T cells.

Figure 1. Increases in both the number and function of T_reg cells have been implicated in the pathogenesis of chronic hepatitis C. Virus-associated regulatory T cell epitopes, homologous to peptide sequences found in the human plasma proteome, induce nT_reg cell activation, conversion of T_eff to iT_reg cells and infectious tolerance (A). Viral epitopes lacking human homology, which are presented by immature DCs, elicit additional HCV-specific iT_reg cells (B). T_reg cells inhibit T_eff cell function by direct, contact-dependent and -independent mechanisms and by indirect mechanisms that affect DC maturation and/or immunostimulatory activity (C).

Figure 2. Contrasting contributions of T_reg cells to the pathogenesis of chronic hepatitis C. An increased ratio of T_reg to T_eff cells impairs spontaneous viral clearance and suppresses liver injury and the pathogenesis of chronic hepatitis C as the disease progresses.