Epithelial control of the human pDC response to extracellular bacteria

Abstract

Plasmacytoid pre-dendritic cells (pDCs) are specialized in responding to nucleic acids, and link innate with adaptive immunity. Although the response of pDCs to viruses is well established, whether pDCs can respond to extracellular bacteria remains controversial. Here, we demonstrate that extracellular bacteria such as Neisseria meningitidis, Haemophilus influenzae, and Staphylococcus aureus activate pDCs to produce IFN-α, TNF-α, IL-6, and to upregulate CD86 expression. We observed that pDCs were present within tonsillar crypts and oro-nasopharyngeal epithelium, where they may contact extracellular bacteria, in situ. Tonsil epithelium-conditioned supernatants inhibited IFN-α, TNF-α, and IL-6 triggered by the direct contact of N. meningitidis or S. aureus with pDCs. However, pDC priming of naive T cells was not affected, suggesting that tonsil epithelium microenvironment limits local inflammation while preserving adaptive immunity in response to extracellular bacteria. Our results reveal an important and novel function of pDCs in the initiation of the mucosal innate and adaptive immunity to extracellular bacteria. Immunol. 2013Immunol. . 43: 1264Immunol. -1273 Immunity to infection 1265 local inflammation to life-threatening septicemia and meningitis. The major location of these bacteria is the human mucosa [2][3][4]. The presence of N. meningitidis at the oro-nasopharynx mucosa was associated with the induction of a naturally acquired immunity able to activate T and B cells [5,6] but the underlying mechanisms by which this response is initiated remain largely unknown. Plasmacytoid pre-dendritic cells (pDCs) play a major role in innate antimicrobial immunity [7,8]. They recognize principally nucleic acids from microbes through endosomal and cytosolic receptors [9,10]. Upon stimulation, pDCs produce large amounts of type-I interferons, IL-6, TNF-α, and upregulate surface costimulatory molecules [7,11]. Although pDCs as well as type-I interferons have an important function in antiviral immunity, their role in the response to extracellular bacterial infection remains highly controversial [9,12]. Here, in an effort to reconstruct the mucosal microenvironment present in the initial steps of antibacterial immunity, we used human primary cells and address the following questions: (i) Can pDCs respond to extracellular bacteria in a mucosal context? (ii) Which is the role of the epithelium in this response and the subsequent T-cell priming? Keywords Results Extracellular bacteria activate pDCs to produce IFN-α, TNF-α, and IL-6 and increase CD86 expressionWe evaluated the direct effect of whole live extracellular bacteria on pDC. Freshly purified pDCs from human blood were cultured for 24 h, and supernatants were collected to quantify cytokine secretion. As expected, pDCs stimulated with CpG secreted high levels of IFN-α, TNF-α, and IL-6 secretion (Fig. 1A). When pDCs were stimulated with the Gram-negative extracellular bacteria N. meningitidis we observed a significant induction of all three cytokines: mean of 10,000 p...

The multifaceted biology of plasmacytoid dendritic cells

“…pDCs that have been developed in the presence of type I IFN resemble Peyer’s patch pDCs, produce inflammatory cytokines, stimulate Th17 cell generation and fail to secrete IFNα after TLR engagement 202 . Therefore, factors expressed at mucosal sites inhibit type I IFN secretion by pDCs, but do not block the ability of pDCs to prime naïve T cells and trigger T Reg and Th17 differentiation 203,204 .…”

Plasmacytoid Dendritic Cells: Neglected Regulators of the Immune Response to Staphylococcus aureus

“…This finding confirmed earlier reports on IFN-α secretion in response to stimulation with S. aureus in a murine DC cell line (9) and initial descriptions of S. aureus -responsive IPCs (10, 11). Michea et al further demonstrated uptake of S. aureus into pDC and secretion of IFN-α, TNF, and IL-6 (6). We further detected pDC-derived IL-1β secretion and low levels of IL-10 in response to S. aureus (7).…”

“…Most importantly, they have made us aware of the fact that there are pDC functions beyond IFN secretion. Despite their versatility only few studies described pDC activation and addressed its role in the host response to Staphylococcus aureus (6–12). Thus, their function in the daily combat with colonizing and infecting S. aureus strains remains to be investigated.…”

Human dendritic cell subsets and function in health and disease

“…cDC in Mycobacterium patients is enhanced by the presence of granzyme-B producing pDC [73]. Michea et al [119] have elegantly shown that both blood and tonsillar pDC are activated by various gram positive and negative bacteria, resulting in production of IFNa and inflammatory cytokines and to priming of CD4 ? naïve T cells.…”

“…Interestingly this study showed that soluble products produced by epithelial cells could greatly reduce the cytokine and IFN response of the pDC in response to bacteria, without affecting their upregulation of co-stimulation markers and their ability to prime naïve T cells. The authors suggested that epithelial cells at mucosal surfaces may restrict the pDC local inflammatory response to bacteria but support their ability to induce an adaptive immune response [119]. The ability of activated pDC to upregulate CCR6 or CCR10 and migrate to mucosal and/or skin epithelia [120] certainly gives them the tools to tackle bacterial infections and is relevant for their role in autoimmune disease.…”