Langerhans cells down-regulate inflammation-driven alveolar bone loss.

Excessive bone resorption is frequently associated with chronic infections and inflammatory diseases. Whereas T cells were demonstrated to facilitate osteoclastogenesis in such diseases, the role of dendritic cells, the most potent activators of naive T cells, remains unclear. Using a model involving inflammation-driven alveolar bone loss attributable to infection, we showed that in vivo ablation of Langerhans cells (LCs) resulted in enhanced bone loss. An increased infiltration of B and T lymphocytes into the tissue surrounding the bone was observed in LC-ablated mice, including receptor activator of NF-κB ligand (RANKL)-expressing CD4(+) T cells with known capabilities of altering bone homeostasis. In addition, the absence of LCs significantly reduced the numbers of CD4(+)Foxp3(+) T-regulatory cells in the tissue. Further investigation revealed that LCs were not directly involved in presenting antigens to T cells. Nevertheless, despite their low numbers in the tissue, the absence of LCs resulted in an elevated activation of CD4(+) but not CD8(+) T cells. This activation involved elevated production of IFN-γ but not IL-17 or IL-10 cytokines. Our data, thus, reveal a protective immunoregulatory role for LCs in inflammation-induced alveolar bone resorption, by inhibiting IFN-γ secretion and excessive activation of RANKL(+)CD4(+) T cells with a capability of promoting osteoclastogenesis.

Dendritic cells in distinct oral mucosal tissues engage different mechanisms to prime CD8+ T cells.

Although oral dendritic cells (DCs) were shown to induce cell-mediated immunity, the identity and function of the various oral DC subsets involved in this process is unclear. In this study, we examined the mechanisms used by DCs of the buccal mucosa and of the lining mucosa to elicit immunity. After plasmid DNA immunization, buccally immunized mice generated robust local and systemic CD8(+) T cell responses, whereas lower responses were seen by lining immunization. A delayed Ag presentation was monitored in vivo in both groups; yet, a more efficient presentation was mediated by buccal-derived DCs. Restricting transgene expression to CD11c(+) cells resulted in diminished CD8(+) T cell responses in both oral tissues, suggesting that immune induction is mediated mainly by cross-presentation. We then identified, in addition to the previously characterized Langerhans cells (LCs) and interstitial dendritic cells (iDCs), a third DC subset expressing the CD103(+) molecule, which represents an uncharacterized subset of oral iDCs expressing the langerin receptor (Ln(+)iDCs). Using Langerin-DTR mice, we demonstrated that whereas LCs and Ln(+)iDCs were dispensable for T cell induction in lining-immunized mice, LCs were essential for optimal CD8(+) T cell priming in the buccal mucosa. Buccal LCs, however, failed to directly present Ag to CD8(+) T cells, an activity that was mediated by buccal iDCs and Ln(+)iDCs. Taken together, our findings suggest that the mechanisms engaged by oral DCs to prime T cells vary between oral mucosal tissues, thus emphasizing the complexity of the oral immune network. Furthermore, we found a novel regulatory role for buccal LCs in potentiating CD8(+) T cell responses.

Directly transfected langerin+ dermal dendritic cells potentiate CD8+ T cell responses following intradermal plasmid DNA immunization.

Dendritic cells (DCs) play a critical role in CD8(+) T cell priming following DNA vaccination. In contrast to other DNA injection routes or immunization with viral vectors, Ag presentation is delayed following needle injection of plasmid DNA into the skin. The contribution of various skin DC subsets to this process is not known. In this study, we show that dermal CD11c(+) cells are the most important transgene-expressing cells following immunization. Using langerin- diphtheria toxin receptor mice we demonstrated that langerin(+) dermal DCs (Ln(+) dDCs) were crucial for generating an optimal CD8(+) T cell response. Blocking migration of skin cells to the lymph node (LN) ablated immunogenicity, suggesting that migration of dDC subsets to the LN is essential for generating immunity. This migration generated a weak Ag-presenting activity in vivo until day 5 postimmunization, which then increased dramatically. We further found that Ln(+) dDCs and dDCs were the only DC populations directly presenting Ag to CD8(+) T cells ex vivo during the initial 8-d period postimmunization. This activity changed on the following days, when both skin DCs and LN-resident DCs were able to present Ag to CD8(+) T cells. Taken together, our in vivo and ex vivo results suggest that activation of CD8(+) T cells following intradermal plasmid DNA immunization depends on directly transfected Ln(+)dDCs and dDCs. Moreover, the type of DCs presenting Ag changed over time, with Ln(+)dDCs playing the major role in potentiating the initial CD8(+) T cell response.