Human vaginal mucosa is the major entry site of sexually transmitted pathogens and thus has long been attractive as a site for mounting mucosal immunity. It is also known as a tolerogenic microenvironment. Here, we demonstrate that immune responses in the vagina are orchestrated by the functional diversity of four major antigen-presenting cell (APC) subsets. Langerhans cells (LCs) and CD14− lamina propria (LP)-DCs polarize CD4+ and CD8+ T cells toward Th2, whereas CD14+ LP-DCs and macrophages polarize CD4+ T cells toward Th1. Both LCs and CD14− LP-DCs are potent inducers of Th22. Due to their functional specialties and the different expression levels of pattern-recognition receptors on the APC subsets, microbial products do not bias them to elicit common types of immune responses (Th1 or Th2). To evoke desired types of adaptive immune responses in the human vagina, antigens may need to be targeted to proper APC subsets with right adjuvants.

BackgroundDendritic cells localize throughout the body, where they can sense and capture invading pathogens to induce protective immunity. Hence, harnessing the biology of tissue-resident dendritic cells is fundamental for the rational design of vaccines against pathogens.MethodsHerein, we characterized the transcriptomes of four antigen-presenting cell subsets from the human vagina (Langerhans cells, CD14- and CD14+ dendritic cells, macrophages) by microarray, at both the transcript and network level, and compared them to those of three skin dendritic cell subsets and blood myeloid dendritic cells.ResultsWe found that genomic fingerprints of antigen-presenting cells are significantly influenced by the tissue of origin as well as by individual subsets. Nonetheless, CD14+ populations from both vagina and skin are geared towards innate immunity and pro-inflammatory responses, whereas CD14- populations, particularly skin and vaginal Langerhans cells, and vaginal CD14- dendritic cells, display both Th2-inducing and regulatory phenotypes. We also identified new phenotypic and functional biomarkers of vaginal antigen-presenting cell subsets.ConclusionsWe provide a transcriptional database of 87 microarray samples spanning eight antigen-presenting cell populations in the human vagina, skin and blood. Altogether, these data provide molecular information that will further help characterize human tissue antigen-presenting cell lineages and their functions. Data from this study can guide the design of mucosal vaccines against sexually transmitted pathogens.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0098-y) contains supplementary material, which is available to authorized users.

Dendritic cells (DCs) are major antigen presenting cells (APCs) that can initiate and control host immune responses toward either immunity or tolerance. These features of DCs, as immune orchestrators, are well characterized by their tissue localizations as well as by their subset-dependent functional specialties and plasticity. Thus, the level of protective immunity to invading microbial pathogens can be dependent on the subsets of DCs taking up microbial antigens and their functional plasticity in response to microbial products, host cellular components and the cytokine milieu in the microenvironment. Vaccines are the most efficient and cost-effective preventive medicine against infectious diseases. However, major challenges still remain for the diseases caused by sexually-transmitted pathogens, including HIV, HPV, HSV and Chlamydia. We surmise that the establishment of protective immunity in the female genital mucosa, the major entry and transfer site of these pathogens, will bring significant benefit for the protection against sexually-transmitted diseases. Recent progresses made in DC biology suggest that vaccines designed to target proper DC subsets may permit us to establish protective immunity in the female genital mucosa against sexually-transmitted pathogens.

Dectin-1 is expressed on myeloid-derived antigen-presenting cells and plays an important role in host immunity against microbial infections. We here demonstrate for the first time that human plasmacytoid dendritic cells (pDCs) express functional Dectin-1. Dectin-1 could deliver intracellular signals to activate pDCs through Syk. As results of activation, pDCs upregulated surface expression of HLA-DR and co-stimulatory molecules. However, pDCs expressed lower levels of CD80, CD86, and CCR7 compared to pDCs activated via TLR9. Signaling via Dectin-1 also induced pDCs to secrete cytokines (IL-6, IFNα, and TNFα) and chemokines (IL-1β, IP-10, IL-8, MIP-1α, and MIP-1β). Most notably, pDCs activated via Dectin-1 secreted greater amount of IL-1β than pDCs activated via TLR9. Dectin-1 stimulated pDCs selectively upregulated inflammation-related gene signatures. We further demonstrated that pDCs activated via Dectin-1 could polarize CD8+ T cells toward IL-10-producing regulatory CD8+ T cells. Activation of pDCs, but not mDCs, via Dectin-1 also resulted in enhanced Th2 type CD4+ T cell responses as well as B cell differentiation into plasmablasts, and this was partly dependent on IL-1β secreted from pDCs. Therefore, we conclude that Dectin-1 expressed on human pDCs possesses unique function to control host immune responses.