A look behind closed doors: interaction of persistent viruses with dendritic cells

Abstract

Persistent infections with HIV, hepatitis B virus and hepatitis C virus are major causes of morbidity and mortality worldwide. As sentinels of the immune system, dendritic cells (DCs) are crucial for the generation of protective antiviral immunity. Recent advances in our understanding of the role of DCs during infection with these viruses provide insights into the mechanisms used by these viruses to exploit DC function and evade innate and adaptive immunity. In this Review we highlight the current knowledge about the interaction between DCs and these viruses and the underlying mechanisms that might influence the outcome of viral infections.

Figure 1. Function of dendritic cells (DCs) in viral immune response

Following uptake of viral antigen, myeloid and plasmacytoid DC subsets (mDC, pDC) migrate to lymphoid tissue to prime naïve CD4+ and CD8+ T cells. In addition, activated DCs produce a range of cytokines, such as IFN-α, IL-12 and IL-15 that in turn activate natural killer (NK) cells and influence T-cell survival and differentiation. Depending on the cytokine signal, CD4+ T cells differentiate into Th1 or Th2 type CD4+ T cells. Th1 mediated IFN-γ secretion stimulates the activation of cytotoxic CD8+ T cells (CTLs) and IgG production in B cells. Th2 mediated cytokine production acts on B cells to simulate IgG production but also has the capacity to inhibit activation of Th1 type T cells. Virus-specific antibodies can be neutralizing, preventing viral re-infection. NK cells and CTLs inhibit viral replication through secretion of IFN-γ or lysis of viral infected cells through the release of cytotoxins (perforin, granzymes). In addition, pDCs are characterized by their ability to produce large amounts of type I IFNs in response to many viruses and, thereby, produces a first strong wave of IFN-α, which not only inhibits viral replication but also is a potent enhancer for NK cell-mediated cytoxicity.

Figure 2. Antigen presentation in the liver results in T cell tolerance

The liver sinusoid is lined by a fenestrated endothelium (liver sinusoidal endothelial cells, LSEC). Kupffer cells (KCs) and immature dendritic cells (DCs) are found in the sinusoids. Hepatic stellate cells (HSC) are located in the sub-endothelial space, known as the Space of Dissé. T cells that recognize antigen in the liver are exposed to immunosuppressive cytokines (IL-10 and TGF-β) that are synthesized by KCs, LSECs and DCs. Interaction of naïve T cells with LSEC results in differentiation of T cells into CD4+ regulatory T cells and impaired cytotoxic CD8+ T cells, followed by cell death. Hepatotropic viruses appear to be captured by DCs and/or LSECs in process that probably involves DC-SIGN or DC-SIGNR (for HCV) or other not yet defined cell-surface molecules (for HBV) for subsequent transfer to the underlying hepatocytes or viral particles may be internalized by hepatic DCs and LSECs for processing and presentation to naïve T cells (Adapted from and 133).