Distinct activation of primary human BDCA1(+) dendritic cells upon interaction with stressed or infected ß cells.

Derailment of immune responses can lead to autoimmune type 1 diabetes, and this can be accelerated or even induced by local stress caused by inflammation or infection. Dendritic cells (DCs) shape both innate and adaptive immune responses. Here, we report on the responses of naturally occurring human myeloid BDCA1(+) DCs towards differentially stressed pancreatic ß cells. Our data show that BDCA1(+) DCs in human pancreas-draining lymph node (pdLN) suspensions and blood-derived BDCA1(+) DCs both effectively engulf ß cells, thus mimicking physiological conditions. Upon uptake of enterovirus-infected, but not mock-infected cells, BDCA1(+) DCs induced interferon (IFN)-α/ß responses, co-stimulatory molecules and proinflammatory cytokines and chemokines. Notably, induction of stress in ß cells by ultraviolet irradiation, culture in serum-free medium or cytokine-induced stress did not provoke strong DC activation, despite efficient phagocytosis. DC activation correlated with the amount of virus used to infect ß cells and required RNA within virally infected cells. DCs encountering enterovirus-infected ß cells, but not those incubated with mock-infected or stressed ß cells, suppressed T helper type 2 (Th2) cytokines and variably induced IFN-γ in allogeneic mixed lymphocyte reaction (MLR). Thus, stressed ß cells have little effect on human BDCA1(+) DC activation and function, while enterovirus-infected ß cells impact these cells significantly, which could help to explain their role in development of autoimmune diabetes in individuals at risk.

Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells.

BACKGROUND: The aryl hydrocarbon receptor (AhR) is a nuclear receptor and transcriptional regulator with pleiotropic effects. The production of potent AhR ligands by Malassezia yeasts, such as indirubin, indolo[3,2-b]carbazole (ICZ), tryptanthrin and malassezin, has been associated with the pathogenesis of seborrhoeic dermatitis and pityriasis versicolor. Antigen-presenting cells in the skin can encounter microbes in the presence of these bioactive metabolites that could potentially modulate their function. OBJECTIVES: To study the effects of the aforementioned naturally occurring ligands on AhR activation and Toll-like receptor (TLR)-induced maturation in human monocyte-derived dendritic cells (moDCs). METHODS: These indoles were screened for AhR activation capacity in moDCs employing CYP1A1 and CYP1B1 induction as read out and for their effects on the function of moDCs after TLR-ligand stimulation. RESULTS: Indirubin and ICZ were the most potent AhR ligands and were selected for subsequent experiments. Concurrent exposure of moDCs to indirubin or ICZ together with TLR agonists significantly augmented the AhR-mediated CYP1A1 and CYP1B1 gene expression. Additionally, mature DCs that were subsequently stimulated with AhR ligands showed increased AhR target gene expression. Moreover, these ligands limited TLR-induced phenotypic maturation (CD80, CD83, CD86, MHC II upregulation) of moDCs, reduced secretion of the inflammatory cytokines interleukin (IL)-6 and IL-12, and decreased their ability to induce alloreactive T-lymphocyte proliferation. CONCLUSIONS: These results demonstrate that AhR agonists of yeast origin are able to inhibit moDC responses to TLR ligands and that moDCs can adapt through increased transcription of metabolizing enzymes such as CYP1A1 and CYP1B1.