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.

To explore the mechanism behind the association between HSV-2 and HIV-1 acquisition, we performed in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions on and off antiviral therapy. CD4+ and CD8+ T cells, and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even in the context of daily antiviral therapy. The CD4+ T cells that persisted reacted to HSV-2 antigen, were enriched for CCR5 expression, and were also contiguous to DCs expressing CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed increased concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies as compared to control skin biopsies. The persistence and enrichment of HIV-receptor-positive inflammatory cells in the genitalia help explain the failure of anti-HSV-2 therapy to reduce HIV acquisition.