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Background: The vitamin D metabolite 1,25(OH)2D3 (VitD3) is a potent immunosuppressive drug and, among others, is used for topical treatment of psoriasis. A proposed mechanism of VitD3-mediated suppression is priming of dendritic cells (DCs) to induce regulatory T (Treg) cells., Objective: Currently, there is confusion about the phenotype of VitD3-induced Treg cells and the DC-derived molecules driving their development. We investigated Treg cell induction after VitD3 priming of 2 distinct skin DC subsets: Langerhans cells (LCs) and dermal dendritic cells (DDCs)., Methods: LCs and DDCs primed with VitD3 were cocultured with allogeneic naive T cells. The phenotype and function of the DCs and induced T cells were analyzed., Results: Both VitD3-primed DC subtypes induced T cells with regulatory activity. Unexpectedly, whereas the Treg cell populations generated by VitD3-primed LCs were CD25(hi)CD127(lo) forkhead box protein 3 (Foxp3)-positive cells, which meet the criteria of classical inducible Treg cells, the T cells developing in response to VitD3-primed DDCs were Foxp3(-) T(R)1 cells expressing IL-10. Inhibition experiments revealed that LC-derived TGF-β is a key factor in the induction of Foxp3(+) Treg cells, whereas DDC-derived IL-10 is important for the induction of IL-10(+) T(R)1 cells., Conclusion: Thus we report the novel finding that distinct but closely related DC subsets are differentially programmed by VitD3 to support development of either TGF-β-dependent Foxp3(+) Treg cells or IL-10-dependent IL-10(+) Treg cells., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Dendritic cells (DCs) can act both as innate cells in host defense and as antigen-presenting cells for naive T cells in adaptive immunity. These functions, among others, are determined by the level of production of particular cytokines. Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by an initial phase predominated by T(H)2 cytokines that switches into a second, more chronic T(H)1-dominated eczematous phase., Objective: To assess to what extent the AD phenotype is associated with an aberrant phenotype and function of DCs., Methods: Classic CD1c(+)/blood DC antigen (BDCA)-1(+) myeloid (m) DCs and CD304(+)/BDCA4(+) plasmacytoid (p) DCs, the natural IFN-producing cells, were isolated from peripheral blood of patients with AD and healthy controls and analyzed for their phenotype and function., Results: Purified CD1c(+)/BDCA1(+) mDCs from patients with AD showed a selective and dramatic reduction of IL-12p70 and TNF-alpha release. IL-12p70 reduction was attributed to a defective expression of both IL-12p35 and IL-12p40 subunits. Accordingly, mature CD1c(+)/BDCA1(+) mDCs from patients with AD induced considerably less IFN-gamma-producing and more IL-4-producing T(H) cells compared with mDCs from healthy controls. In addition, CD304(+)/BDCA4(+) pDCs from patients with AD produced significantly lower levels of IFN-alpha compared with healthy controls., Conclusion: Myeloid DCs and pDCs from patients with AD show defective IL-12, TNF-alpha, and IFN-alpha production, which may contribute to increased susceptibility to infection and to the maintenance of the T(H)2 cell-mediated allergic state in patients with AD.

Background: Lactobacilli are probiotic bacteria that are frequently tested in the management of allergic diseases or gastroenteritis. It is hypothesized that these probiotics have immunoregulatory properties and promote mucosal tolerance, which is in part mediated by regulatory T cells (Treg cells). On the basis of pathogenic or tissue-specific priming, dendritic cells (DC) acquire different T cell-instructive signals and drive the differentiation of naive T H cells into either T H 1, T H 2, or regulatory effector T cells., Objective: We studied in what way different species of lactobacilli prime human DCs for their ability to drive Treg cells., Methods: Human monocyte-derived DCs were cultured in vitro with lactobacilli of different species., Results: Two different species of lactobacilli, Lactobacillus reuteri and Lactobacillus casei , but not Lactobacillus plantarum, prime monocyte-derived DCs to drive the development of Treg cells. These Treg cells produced increased levels of IL-10 and were capable of inhibiting the proliferation of bystander T cells in an IL-10-dependent fashion. Strikingly, both L reuteri and L casei , but not L plantarum , bind the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). Blocking antibodies to DC-SIGN inhibited the induction of the Treg cells by these probiotic bacteria, stressing that ligation of DC-SIGN can actively prime DCs to induce Treg cells., Conclusions: The targeting of DC-SIGN by certain probiotic bacteria might explain their beneficial effect in the treatment of a number of inflammatory diseases, including atopic dermatitis and Crohn's disease.

Background: Human studies have demonstrated that allergen immunotherapy induces memory suppressive responses and IL-10 production by allergen-specific T cells. Previously, we established a mouse model in which allergen immunotherapy was effective in the suppression of allergen-induced asthma manifestations., Objective: In this study, we examined whether immunotherapy induces a long-lasting effect and investigated the role of IL-10 in successful immunotherapy., Methods: Ovalbumin-sensitized BALB/c mice were treated with 3 injections of ovalbumin (1 mg, subcutaneous) on alternate days. After a short interval (1 week) and after a long interval (5 weeks), mice were challenged by ovalbumin inhalation, and subsequently, airway reactivity, airway eosinophilia, ovalbumin-specific IgE, and T(H)2 cytokine profile were measured. Flow cytometry and blocking of IL-10 receptors in vivo were used to gain insight in the role of IL-10 in the beneficial effects of allergen immunotherapy., Results: After a long interval between ovalbumin immunotherapy and ovalbumin challenge, the development of airway eosinophilia and hyperresponsiveness to methacholine were as strongly suppressed as after a short interval. These suppressive effects coincided with significantly reduced serum ovalbumin-specific IgE levels and T(H)2 cytokine production. On immunotherapy, the IL-5:IL-10 ratio in the bronchoalveolar lavage fluid shifted toward IL-10. In ovalbumin-restimulated lung cell and thoracic lymph node cultures from these mice, IL-5 levels dramatically decreased, whereas the percentage of IL-10(+)CD4(+) T cells was not affected. Finally, in mice treated with mAb against IL-10 receptors, the beneficial effects of immunotherapy were largely abrogated., Conclusion: These data demonstrate that allergen immunotherapy induces a memory suppressive effect in which IL-10 is essential.

Background: Increasing evidence indicates a prominent role of allergen-specific TH2 cells, with high IL-4 and IL-5 production and low interferon-gamma production, in the regulation of IgE and eosinophil production in allergic disorders. However, most studies have concentrated on T cells reactive with inhalation allergens, whereas little is known about the properties of food allergen-reactive T cells., Objectives: In this study we therefore characterized peanut-specific T cells, cloned from a patient with severe peanut allergy., Methods: Peripheral blood mononuclear cells from patients with peanut allergy and nonallergic individuals were stimulated with crude peanut extract (CPE) to compare the proliferative responses and to select a suitable patient for the cloning of CPE-specific T cells. The resultant panel of CPE-reactive T-lymphocyte clones was serologically phenotyped by flow cytometry and analyzed for cytokine secretion by ELISA., Results: The patients' peripheral blood mononuclear cells showed a dose-dependent proliferation response to CPE, which was significantly higher (p < 0.05) than in peripheral blood mononuclear cells of nonallergic donors. The CPE-specific T-lymphocyte clones generated from the selected patient were all CD4+/CD8- T helper cells with a TH2 cytokine profile, secreting high amounts of IL-4 and IL-5, but little or no interferon-gamma., Conclusions: This study demonstrates that peanut-specific T cells do occur in the peripheral blood of patients with peanut allergy and suggests an increased frequency of these T cells in patients compared with nonallergic control subjects. The CD4+ phenotype and the TH2 cytokine profile of the CPE-specific T-lymphocyte clones suggest a functional role of allergen-specific TH2 cells in the pathophysiology of food allergy, similar to the function of inhalation allergen-specific TH2 cells.