Vaginal Submucosal Dendritic Cells, but Not Langerhans Cells, Induce Protective Th1 Responses to Herpes Simplex Virus-2

Abstract

Herpes simplex virus (HSV) type 2 infection occurs primarily at the genital mucosal surfaces and is a leading cause of ulcerative lesions. Despite the availability of animal models for HSV-2 infection, little is known regarding the mechanism of immune induction within the vaginal mucosa. Here, we examined the cell types responsible for the initiation of protective Th1 immunity to HSV-2. Intravaginal inoculation of HSV-2 led to a rapid recruitment of submucosal dendritic cells (DCs) to the infected epithelium. Subsequently, CD11c+ DCs harboring viral peptides in the context of MHC class II molecules emerged in the draining lymph nodes and were found to be responsible for the stimulation of IFNγ secretion from HSV-specific CD4+ T cells. Other antigen-presenting cells including B cells and macrophages did not present viral peptides to T cells in the draining lymph nodes. Next, we assessed the relative contribution to immune generation by the Langerhans cells in the vaginal epithelium, the submucosal CD11b+ DCs, and the CD8α+ lymph node DCs. Analysis of these DC populations from the draining lymph nodes revealed that only the CD11b+ submucosal DCs, but not Langerhans cell–derived or CD8α+ DCs, presented viral antigens to CD4+ T cells and induced IFNγ secretion. These results demonstrate a previously unanticipated role for submucosal DCs in the generation of protective Th1 immune responses to HSV-2 in the vaginal mucosa, and suggest their importance in immunity to other sexually transmitted diseases.

Langerhans cells and viral immunity

“…Also consistent with immunoregulation, the TLR expression profile by LC with low expression of TLR-2 and -4 necessary for bacterial recognition results in selective unresponsiveness of LC to bacteria compared with viruses and may contribute to tolerance to bacterial commensals [8,9]. In some cases dermal DC may play the immunostimulatory role previously attributed to LC [10][11][12]. Recently, a distinct subset of dermal DC was identified in mouse that expresses langerin and this subset might be important for immunostimulation [13][14][15] although so far, little is known about their function and whether a similar subset exists in humans.…”

“…However, others and we have recently shown that LC are not the cells presenting HSV antigen to CD8 1 T cells in lymph nodes. After epidermal scarification with the virus, it was observed that CD8 1 DC present HSV antigens to CD8 1 T cells in draining lymph nodes 24 h after infection [57], and after vaginal inoculation of HSV, dermal DC were demonstrated to present HSV antigen to CD4 1 T cells [12]. The apparent paradox of initial HSV antigen uptake by LC but presentation by another DC subtype may be explained by transfer of the antigens from one DC subtype to another [57].…”

Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

“…It was recently reported that the migration of dermal DCs to dCLNs takes slightly more than 90 min, whereas LC migration can take more than 24 h [8]. Therefore, to evaluate the role of migrating skin DCs in antigen presentation, we removed the ear 90 min after HEL inoculation.…”

“…Although Langerhans cells (LCs) have been shown to be potent APCs in vitro [3], in vivo approaches have produced conflicting data regarding their role in T-cell priming [4,5]. Dermal DCs are also migrating DCs that colonize lymph nodes more rapidly than LCs [6,7], and different roles for skin DC subsets in T-cell priming have been reported [7][8][9]. Skin immunization has yielded controversial data, with some reports supporting a Th2-type response [10,11] and others a Th1-type response [12,13].…”

“…in the ear using various HEL doses. Figure 1A shows the dose-dependent proliferation of HEL-specific T cells in draining cutaneous lymph nodes (dCLNs), which was observed after inoculation in the ear using as little as 0.3 mg HEL per mouse.It was recently reported that the migration of dermal DCs to dCLNs takes slightly more than 90 min, whereas LC migration can take more than 24 h [8]. Therefore, to evaluate the role of migrating skin DCs in antigen presentation, we removed the ear 90 min after HEL inoculation.…”