Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ

Abstract

Dendritic cells (DCs) are powerful APCs capable of activating naive lymphocytes. Of the DC subfamilies, plasmacytoid DCs (pDCs) are unique in that they secrete high levels of type I IFNs in response to viruses but their role in inducing adaptive immunity remains divisive. In this study, we examined the importance of pDCs and their ability to recognize a virus through TLR9 in immunity against genital HSV-2 infection. We show that a low number of pDCs survey the vaginal mucosa at steady state. Upon infection, pDCs are recruited to the vagina and produce large amounts of type I IFNs in a TLR9-dependent manner and suppress local viral replication. Although pDCs are critical in innate defense against genital herpes challenge, adaptive Th1 immunity developed normally in the absence of pDCs. Thus, by way of migrating directly into the peripheral mucosa, pDCs act strictly as innate antiviral effector cells against mucosal viral infection in situ.

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

“…WT 129Sv mice produce much more IFN than do WT C57BL/6 mice, and activities dependent on type I IFN in 129Sv mice may not show the same dependency in other mouse strains. In support of this idea, it has recently been reported that TLR9 Ϫ/Ϫ mice on a mixed 129Sv ϫ C57 background are impaired with respect to clearance of genital herpes through a mechanism dependent on pDC-derived type I IFN (36); in the present study, however, we found that TLR9 Ϫ/Ϫ mice on a C57BL/6 background were indistinguishable from WT mice in the same model. Therefore, to fully evaluate the relative contributions of the types I and III IFN systems in antiviral defense, and to look for possible redundancy in this system, it will be necessary to study the IFNAR Ϫ/Ϫ and IL-28R␣ Ϫ/Ϫ mice on the same genetic background and to generate IFNAR/IL-28R␣ double-deficient mice.…”

“…It has been suggested that pDCs are important for protection against genital herpes (36), and that HSV-2 replicates exclusively in vaginal epithelial cells in the model used in this study (44). We found that pDCs and epithelial cells responded to IFN-, whereas few other cell types did.…”

Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue

“…Given the rapid onset of CCL2 secretion (within 24 h of HSV-2 challenge), we reasoned that CCR2 ligands must be induced by innate signals. It is known that local type I IFNs are secreted rapidly following HSV-2 infection (19). In addition, type I IFNs have been shown to induce CCR2 ligand expression and recruitment of monocytes (20).…”

Enemy at the gates: dendritic cells and immunity to mucosal pathogens

“…CD11b + submucosal DC, but not vaginal LC or CD8α + lymph node-resident DC, were shown to control mucosal HSV-2 infection by inducing T H 1 T-cell-mediated antiviral immunity [46]. In response to intravaginal HSV-2 infection, pDC are rapidly recruited to the vaginal mucosa where they provide protection from lethal challenge through the production of copious amounts of IFN-α initiated by TLR9-based recognition of viral CpG oligodeoxynucleotides [51,52]. In support of these findings, human herpetic lesions contain vast infiltration of uninfected pDC, which readily associated with T and NK cells in vivo and stimulated autologous T-cell proliferation in vitro [53].…”

“…An additional, but by no means exclusive mechanism for the heightened IFN-α/β response of pDC is their ability to sequester TLR signaling complexes, as illustrated by the retention of CpG DNA-TLR9 within the endosomal vesicles for extended periods of time over that seen in cDC, allowing for continual TLR activation and IRF signaling [70]. pDC recognition of dsDNA genomic intermediates of replicating DNA viruses via TLR9 accounts for the detection of HSV and murine cytomegalovirus [51,[71][72][73]. Interestingly, TLR9-mediated recognition of the malarial byproduct hemozoin derived from Plasmodium falciparum and subsequent production of IL-12 and IFN-γ by DC have been implicated in the proinflammatory cytokinemia associated with acute disease and related sepsis by enhancing TLR expression-and 'priming'-associated signaling pathways leading to hyperresponsiveness to further bacterial or parasitic TLR activation [74,75].…”