Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion

Abstract

Adaptive cellular immunity is required to clear HSV-1 infection in the periphery. Myeloid dendritic cells (DCs) are the first professional Ag-presenting cell to encounter the virus after primary and secondary infection and thus the consequences of their infection are important in understanding the pathogenesis of the disease and the response to the virus. Following HSV-1 infection, both uninfected and infected human DCs acquire a more mature phenotype. In this study, we demonstrate that type I IFN secreted from myeloid DC mediates bystander activation of the uninfected DCs. Furthermore, we confirm that this IFN primes DCs for elevated IL-12 p40 and p70 secretion. However, secretion of IFN is not responsible for the acquisition of a mature phenotype by HSV-1-infected DC. Rather, virus binding to a receptor on the cell surface induces DC maturation directly, through activation of the NF-κB and p38 MAPK pathways. The binding of HSV glycoprotein D is critical to the acquisition of a mature phenotype and type I IFN secretion. The data therefore demonstrate that DCs can respond to HSV exposure directly through recognition of viral envelope structures. In the context of natural HSV infection, the coupling of viral entry to the activation of DC signaling pathways is likely to be counterbalanced by viral disruption of DC maturation. However, the parallel release of type I IFN may result in paracrine activation so that the DCs are nonetheless able to mount an adaptive immune response.

LIGHTing up dendritic cell activation: Immune regulation and viral exploitation

“…HSV-1 gD antagonises binding of LIGHT to HVEM (Mauri et al, 1998), suggesting that HVEM cross-linking by HSV-1 could result in similar downstream signalling and functional changes as LIGHT. Indeed, similar to the findings of Zou and Hu with LIGHT, binding and infection of DC by HSV-1 also results in activation of NF-kB pathways and upregulation of CD86 (Pollara et al, 2004). Notably, gD is central to these changes, as neutralising gD on HSV-1 virions ablates CD86 upregulation and NF-kB activation, whereas addition of recombinant gD to DC induces expression of CD86 (Pollara et al, 2004 and unpublished observations).…”

“…The signalling consequences of this interaction may enhance viral replication through activation of NF-kB (Patel et al, 1998), as well as preventing apoptosis by not activating JNK MAPK (Handley et al, 2005). Alternatively, gD may be expressed on the cell surface of infected DC (Pollara et al, 2004), and subsequently bind to HVEM, or a related receptor. This process may prevent binding of LIGHT to its receptor, either due to direct competition between gD and LIGHT (Mauri et al, 1998), or by inducing downregulation of the receptor.…”

Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses

“…Although IFN-␣ production by pDC contributes to its effects on a number of immune cells (31,35), surprisingly, the synergy between pDC and mDC that we observed appeared to be largely due to cell-to-cell contact. Addition of exogenous IFN-␣ did not cause mDC activation in vitro, and neutralizing Abs against IFN-␣ did not block pDC-dependent mDC activation.…”

Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

“…IL-12 production results in the polarization of the ensuing adaptive immune responses, promoting a cellmediated phenotype through its ability to influence the development of type I helper T cells from the common precursor cell population (46). The majority of IL-12 produced in response to FPV also originated in the FL-expanded cultures, suggesting that its secretion is dependent on pDCs, either directly through their ability to actively secrete IL-12 (9) and/or indirectly through the provision of factors, such as type I IFNs which are required for IL-12 secretion from other cell types (9,17,42). When the identity of the subset of DCs secreting IL-12 within the FL-expanded culture was defined, it was clear that the cDCs within this culture produced the majority of the IL-12 although the pDC subset was also clearly capable of this.…”