Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment

Figure 1 Crosstalk among immune cells and cytokines in hepatitis B virus infection. The complex interactions among immune cells and cytokines in chronic hepatitis B are shown. Hepatitis B virus (HBV)-specific CD8⁺ T-cells are activated by monocytes and CD4⁺ T-cells, followed by recruitment and activation of macrophages by active CD8⁺ T-cells. The activation of natural killer (NK) T-cells is induced by Kupffer cells, which activate NK cells and hepatic stellate cells (HSCs). Suppressive Tregs, Bregs and Kupffer cells induce the functional impairment of CD8⁺ T cells, CD4⁺ T-cells and NK cells. Moreover, Treg cells, Kupffer cells and myeloid-derived suppressor cells can lead to the exhaustion of CD8⁺ T-cells and NK cells. Inflammatory and inhibitory cytokines, including Monocyte chemoattractant protein-1, tumor necrosis factor-α, interferon-γ, interleukin (IL)-4, IL-6, IL-12, IL-13, IL-17, IL-10, and transforming growth factor-β, are involved in the crosstalk among immune cells. The activation of HSCs in sinusoids is induced by a complement protein such as C5a. Finally, decreasing epigenetic modification and function of HBV-specific CD8⁺ T-cells inhibits the immune control of HBV. PD-1: Programmed death 1; CTLA-4: Cytotoxic T-lymphocyte antigen-4; IL: Interleukin; TNF-α: Tumor necrosis factor-α; TGF-β: Transforming growth factor β; IFN-γ: Interferon-γ; HSC: Hepatic stellate cell; MDSC: Myeloid-derived suppressor cells; NK: Natural killer.