Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C

Abstract

Hepatitis C virus (HCV) is a small, enveloped RNA virus and a major cause of chronic liver disease. Resolution of primary HCV infections depends upon the vigorous responses of CD4⁺ and CD8⁺ T cells to multiple viral epitopes. Although such broad-based responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Ostensibly, a variety of factors contribute to the diminished T cell responses observed in chronic, HCV-infected patients including impaired dendritic cell function and the induction of CD4⁺ FoxP3⁺ regulatory T cells. Overwhelming evidence suggests that the complex interaction of dendritic cells and regulatory T cells plays a critical role in the pathogenesis of chronic hepatitis C.

Keywords: FoxP3+ regulatory T cells; chronic liver disease; dendritic cells; hepatitis C; tolerance.

Figure 1. Hepatitis C virus: structure and genomic organization. The viral genome is enclosed within the core protein and surrounded by an envelope composed of lipid and glycoproteins (A). HCV is a small, enveloped virus with a single-stranded, positive-sense RNA genome that is ~9,600 nucleotide bases long and consists of a single open reading frame. The 5′, ~340 nucleotide long, non-translated region (NTR) functions as an internal ribosome entry site that binds ribosomes in close proximity to the translation start codon. The HCV genome encodes a ~3,000 amino acid poly-protein precursor that is cleaved co- and post- translationally by cellular and viral proteases into ten protein products: C, core; E1 and E2, envelope; NS, nonstructural proteins (NS1–NS5). The function of each cleavage product is shown (B).

Figure 2. FoxP3⁺ T_reg cell production in the thymus and periphery. Natural (n)T_reg cells are generated by high-avidity selection in the thymus. Inducible (i)T_reg cells derive from antigen-stimulated naïve T cells in the periphery. nT_reg cells can promote iT_reg cell development by cytokine-dependent mechanisms (infectious tolerance).

Figure 3. Mechanisms mediating T_reg cell suppression. FoxP3⁺ T_reg cells suppress T_eff cell activity (A). T_reg cells inhibit T_eff cell activity by multiple contact-dependent and -independent mechanisms described in the text. FoxP3⁺ T_reg cells impair DC function (B). Similarly, T_reg cells impair DC maturation and function by mechanisms described in the text.

Figure 4. Immune suppression mechanisms in HCV infection. Both the number and functions of circulating mDCs and pDCs are diminished in cases of chronic hepatitis C. Immature DCs promote the expansion and function of FoxP3⁺ T_reg cells. T_reg cells, in turn, suppress CD4⁺ and CD8⁺ T cell, NK cell, NKT cell, B cell, macrophage and DC activities. Red and blue arrows indicate activation and suppression, respectively.