Langerhans Cell-like Dendritic Cells Research Articles

Treatment Outcomes of Langerhans Cell Histiocytosis: A Retrospective Study.

Background and Objectives: Langerhans cell histiocytosis (LCH) is a rare disease characterized by the infiltration of one or more organs by Langerhans cell-like dendritic cells. LCH often involves the bone, and its clinical evidence is limited. The purpose of this study is to report on the treatment of LCH at our institution and to add to the evidence for LCH. Materials and Methods: We reviewed six cases of LCH treated in our hospital between November 2005 and February 2016. Patient age at the first visit, sex, site of origin, symptoms, image tools used for diagnosis, biopsy site, complications, treatment, and final clinical outcome were evaluated. The median follow-up period was 41 months. Results: The median patient age at the first visit was 13.5 years. Three male and three female individuals were enrolled. Multiple lesions were observed in five cases, and a solitary lesion was observed in one case. Pain was the chief complaint in five cases. Radiography was the most commonly used imaging tool. Bone scintigraphy or magnetic resonance imaging and positron emission tomography-computed tomography were also used to diagnose systematic LCH. Biopsy of the femur was performed in two cases, and biopsy of the tibia, lumbar vertebrae, rib, and radius was performed in one case each. Regarding comorbidities, one case of hepatitis B and one case of autism were observed. Chemotherapy was initiated in two patients. The other four patients were observed naturally. Continuous disease-free survival was observed in five patients. One patient remained alive but not without disease during the final follow-up examination. Conclusion: LCH should be diagnosed as early as possible to treat it appropriately.

A profile of pro-inflammatory cytokine expression in human Delta-1-induced monocyte-derived Langerhans cell-like dendritic cells after stimulation with Toll-like receptor ligands

A profile of pro-inflammatory cytokine expression in human Delta-1-induced monocyte-derived Langerhans cell-like dendritic cells after stimulation with Toll-like receptor ligands

Langerhans cell-like dendritic cells treated with ginsenoside Rh2 regulate the differentiation of Th1 and Th2 cells in vivo

AbstractGinsenoside Rh2 is one of the rare ginsenosides extracted from Panax ginseng C. A. Mey. The anti-allergic activity of ginsenoside Rh2 has been documented in some literature. In this work, an anti-allergic mechanism of ginsenoside Rh2 was investigated by focusing on the differentiation of T cells through Langerhans cells (LCs). Langerhans cell-like dendritic cells (LDCs) were generated in vitro and were used as substitute for LCs.In vivo the mRNA expression for IFN-γ and CXCR3 of T cells was increased after being injected with ginsenoside Rh2-treated LDCs thereby increasing the concentration of IFN-γ in the culture supernatants of CD3+/CD28+ T lymphocytes. However,in vitro, the expression of mRNA for CD40 and CD80 on ginsenoside Rh2-treated LDCs was up-regulated significantly and the endocytic activity of LDCs was down-regulated slightly. These findings indicate that T cells differentiation could be regulated by ginsenoside Rh2 through LDCs in vivo by altering the antigen presenting capacity, maturation and phagocytosis of LDCs.

Betamethasone, but Not Tacrolimus, Suppresses the Development of Th2 Cells Mediated by Langerhans Cell-Like Dendritic Cells.

It is well known that Langerhans cells (LCs) work as the primary orchestrators in the polarization of the immune milieu towards a T helper type 1 (Th1) or T helper type 2 (Th2) response. In this study, we investigated the effects of tacrolimus and betamethasone, each used as topical applications in atopic dermatitis (AD), on Th2 cell development mediated by LCs. LC-like dendritic cells (LDCs) were generated from mouse bone marrow cells and used as substitutes for LCs. Mice were primed with ovalbumin (OVA) peptide-pulsed LDCs, which had been treated with tacrolimus or betamethasone, via the hind footpad. After 5 d, the cytokine response in the popliteal lymph nodes was investigated by enzyme-linked immunosorbent assay. The expression of cell surface molecules on LDCs was investigated via reverse transcriptase polymerase chain reaction. Administration of OVA peptide-pulsed LDCs, which had been treated with betamethasone, inhibited Th2 cell development, as represented by the down-regulation of interleukin-4 production, and also inhibited Th1 cell development, represented by the down-regulation of interferon-γ production. However, tacrolimus-treated LDCs did not induce such inhibition of the development of Th1 and Th2 cells. The inhibition of Th1 and Th2 cell development was associated with the suppression of CD40 and T-cell immunoglobulin, and mucin domain-containing protein (TIM)-4 expression, respectively, in LDCs. These results suggest that the topical application of betamethasone to skin lesions of patients with AD acts on epidermal LCs, and may inhibit the development of Th2 cells, thus being of benefit for the control of AD.

Langerhans cell-like dendritic cells stimulated with an adjuvant direct the development of Th1 and Th2 cells in vivo.

It is well known that Langerhans cells (LCs) work as the primary orchestrators in the polarization of immune responses towards a T helper type 1 (Th1) or Th2 milieu. In this study, we attempted to generate LCs from murine bone marrow cells and elicit a Th1- or Th2-prone immune response through the LCs after stimulation with Th1 or Th2 adjuvant. LCs were generated from murine bone marrow cells using granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and transforming growth factor (TGF)-β, and were obtained as I-A(d) positive cells. Mice were primed with Th1/Th2 adjuvant- and ovalbumin (OVA)-pulsed LCs and then given a booster injection of OVA 2 days later via the hind footpad. Five days after the OVA injection, the cytokine response in the draining popliteal lymph nodes was investigated by reverse transcription-polymerase chain reaction (RT-PCR) flow cytometry and enzyme-linked immunosorbent assay (ELISA). The generated LCs expressed typical LC surface markers, E-cadherin and Langerin, and were classified accordingly as LC-like dendritic cells (LDCs). Administration of Th1 adjuvant, cytosine-phosphate-guanosine (CpG)-DNA- and OVA-pulsed LDCs into the hind footpads of mice induced a Th1-prone immune response, as represented by up-regulation of IFN-γ production and down-regulation of IL-4 production in the lymph node cells. Conversely, Th2 adjuvant, histamine-pulsed LDCs induced a Th2-prone immune response, as represented by up-regulation of IL-4 production and down-regulation of IFN-γ production. These results suggest that LDCs may be used as a substitute for LCs and have the ability to induce the development of Th1 and Th2 cells in vivo. Our experimental system would therefore be useful for screening of inhibitors of Th1/Th2 differentiation in order to control allergic disease.

Histiocytose langerhansienne de l’adulte

Langerhans cell histiocytosis (LCH) is a rare disease characterized by the infiltration of one or more organs by Langerhans cell-like dendritic cells, most often organized in granulomas. The disease has been initially described in children. The clinical picture of LCH is highly variable. Bone, skin, pituitary gland, lung, central nervous system, lymphoid organs are the main organs involved whereas liver and intestinal tract localizations are less frequently encountered. LCH course ranges from a fulminant multisystem disease to spontaneous resolution. Several randomized controlled trials have enable pediatricians to refine the management of children with LCH. Adult LCH has some specific features and poses distinct therapeutic challenges, knowing that data on these patients are limited. Herein, we will provide an overview of current knowledge regarding adult LCH and its management. We will also discuss recent advances in the understanding of the disease, (i.e. the role of BRAF oncogene) that opens the way toward targeted therapies.

Human Beta-Defensin 3 Induces Maturation of Human Langerhans Cell–Like Dendritic Cells: An Antimicrobial Peptide that Functions as an Endogenous Adjuvant

Human beta defensins (hBDs) are antimicrobial peptides that play an important role in innate immune responses at epithelial barriers such as the skin. However, the role that hBDs play in initiating cellular immune responses that contribute to antigen-specific adaptive immunity is not well understood. Here we show that one member of the hBD family, hBD3, can induce maturation and T helper type 1 (Th1) skewing function in human Langerhans cell-like DCs (LC-DCs). Specifically, hBD3 potently induces phenotypic maturation of LC-DCs, including increased expression of CCR7 which mediates functional chemotactic responses to CCL19 and CCL21. HBD3-stimulated LC-DCs induce strong proliferation and IFN-γ secretion by naïve human T cells. HBD3 also induces phenotypic maturation of primary human skin-migratory dendritic cells derived from human skin explants. These results suggest an important role for hBD3 in inducing DC activation, migration, and polarization. Thus hBD3 contributes to the integration of innate and adaptive immune responses in the skin and may be a useful adjuvant for skin immunization and an important factor in the pathophysiology of inflammatory skin diseases.

Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells

AbstractLangerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs). In the present study, we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DCs, but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated and tissue-bound LCH cells selectively express the Notch ligand Jagged 2 (JAG2) and are the only DCs that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DCs, suggesting a functional role of Notch signaling in LCH ontogenesis. JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DCs and was not recapitulated in monocytes. The results of the present study suggest that JAG2-mediated Notch activation confers phenotypic and functional aspects of LCH to DCs; therefore, interference with Notch signaling may be an attractive strategy to combat this disease.

Disruption of E-Cadherin-Mediated Adhesion Induces a Functionally Distinct Pathway of Dendritic Cell Maturation

The maturation of dendritic cells (DCs) after exposure to microbial products or inflammatory mediators plays a critical role in initiating the immune response. We found that maturation can also occur under steady-state conditions, triggered by alterations in E-cadherin-mediated DC-DC adhesion. Selective disruption of these interactions induced the typical features of DC maturation including the upregulation of costimulatory molecules, MHC class II, and chemokine receptors. These events were triggered at least in part by activation of the beta-catenin pathway. However, unlike maturation induced by microbial products, E-cadherin-stimulated DCs failed to release immunostimulatory cytokines, exhibiting an entirely different transcriptional profile. As a result, E-cadherin-stimulated DCs elicited an entirely different T cell response in vivo, generating T cells with a regulatory as opposed to an effector phenotype. These DCs induced tolerance in vivo and may thus contribute to the elusive steady-state "tolerogenic DCs."

Immunopathology of atopic dermatitis

Immunopathology of atopic dermatitis

CCL1-CCR8 Interactions: An Axis Mediating the Recruitment of T Cells and Langerhans-Type Dendritic Cells to Sites of Atopic Skin Inflammation

Atopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10-20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1alpha) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.

Langerhans Cells Stimulated by Mechanical Stress Are Susceptible to Measles Virus Infection

Objective: Measles virus (MV) first infects the human respiratory tract, but the initial target cells are unknown. We examined whether MV infects Langerhans cell-like dendritic cells (LCs) generated from CD14⁺ monocytes in the presence of GM-CSF, IL-4, and TGF-β1. Methods: Cultured LCs were established as described recently [Biochem Biophys Res Commun 2003;306:674–679]. The expression of immunological markers was detected by FACScan. Infection with MV was assessed by syncytia formation, viral-specific fluorescence, and Western blotting. Results: MV did not infect and replicate the freshly established, unstimulated LCs expressing CD1a, E-cadherin and Langerin but not CD83. Also, CD150, a receptor for MV was not expressed on the surface of the LCs. However, LCs stimulated by mechanical stress such as washing and centrifugation became susceptible to MV infection. Conclusion: A subset of mechanically stimulated LCs but not unstimulated immature ones became susceptible to MV. The actual role of Langerhans cells in local immunity seems to be to suppress unfavorable reactions initiated by virus intrusion.

Langerhans cell?like dendritic cells and inflammatory dendritic epidermal cell?like dendritic cells induce distinct T-cell responses

Allergic reactions are driven by the continuous flow of antigen uptake and presentation processes, which are perpetuated mainly by dendritic cells (DCs). Atopic dermatitis (AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated by TH2 cytokines that switches to a second and more chronic TH1-dominated eczematous phase. However, cellular and soluble factors initiating this switch have not been elucidated thus far. In this issue of the Journal, Novak et al (p 949) show with the help of a novel in vitro model that Langerhans cell–like DCs (LC-DCs) and inflammatory dendritic epidermal cell–like DCs (IDEC-DCs) activated via the high affinity receptor for IgE (FcεRI) contribute distinctly to the outcome of T-cell responses in vitro and might therefore have implications on the biphasic nature of AD in vivo. FcεRI-activated LC-DCs release signals that contribute to the recruitment of precursor cells of IDEC-DCs and the induction of an immune response of the TH2 type. In contrast, FcεRI-activated IDEC-DCs produce high amounts of proinflammatory cytokines and chemokines and might amplify the inflammatory immune reaction in the skin of patients with AD in this way. FcεRI-activated IDEC-DCs prime naive T cells into IFN-γ–producing T cells of the TH1 type (see illustration) and release IL-12 and IL-18, which together might lead to the switch of the initial TH2 into an immune response of the TH1 type in AD in vivo. Allergic reactions are driven by the continuous flow of antigen uptake and presentation processes, which are perpetuated mainly by dendritic cells (DCs). Atopic dermatitis (AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated by TH2 cytokines that switches to a second and more chronic TH1-dominated eczematous phase. However, cellular and soluble factors initiating this switch have not been elucidated thus far. In this issue of the Journal, Novak et al (p 949) show with the help of a novel in vitro model that Langerhans cell–like DCs (LC-DCs) and inflammatory dendritic epidermal cell–like DCs (IDEC-DCs) activated via the high affinity receptor for IgE (FcεRI) contribute distinctly to the outcome of T-cell responses in vitro and might therefore have implications on the biphasic nature of AD in vivo. FcεRI-activated LC-DCs release signals that contribute to the recruitment of precursor cells of IDEC-DCs and the induction of an immune response of the TH2 type. In contrast, FcεRI-activated IDEC-DCs produce high amounts of proinflammatory cytokines and chemokines and might amplify the inflammatory immune reaction in the skin of patients with AD in this way. FcεRI-activated IDEC-DCs prime naive T cells into IFN-γ–producing T cells of the TH1 type (see illustration) and release IL-12 and IL-18, which together might lead to the switch of the initial TH2 into an immune response of the TH1 type in AD in vivo.

FcεRI engagement of Langerhans cell–like dendritic cells and inflammatory dendritic epidermal cell–like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro

Background Atopic dermatitis (AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated by T H2 cytokines, which switches into a second T H1-dominated chronic phase. Thus far, the small number of FcεRI-bearing Langerhans cells (LCs) and inflammatory dendritic epidermal cells (IDECs) in the epidermis of patients with AD has hampered a detailed functional analysis and limited our knowledge of these dendritic cells (DCs). Objective We studied FcεRI-mediated mechanisms of LCs and IDECs with the help of a novel in vitro model. Methods Langerhans cell–like dendritic cells (LC-DCs) and inflammatory dendritic epidermal cell–like dendritic cells (IDEC-DCs) bearing FcεRI have been generated from monocytes of the same atopic donor and compared functionally with LCs and IDECs isolated from the skin of patients with AD. Results We found that FcεRI-activated LC-DCs release chemotactic signals, and supernatants of FcεRI-activated LC-DCs increase the migratory capacity of precursor cells of IDECs and naive T cells in vitro. FcεRI-activated IDEC-DCs produce high amounts of proinflammatory cytokines and chemokines and might thereby amplify the inflammatory immune reaction in patients with AD. Furthermore, FcεRI-activated IDEC-DCs prime naive T cells into IFN-γ–producing T cells and release IL-12 and IL-18, which together might lead to the switch of the initial T H2-type immune response into a response of the T H1 type in vivo. Conclusion The present study provides evidence that FcεRI-activated LC-DCs and IDEC-DCs contribute distinctly to the outcome of T-cell responses in vitro and might have implications for the biphasic nature of AD in vivo.

Ultraviolet B radiation suppresses endocytosis, subsequent maturation, and migration activity of langerhans cell-like dendritic cells.

Langerhans cells capture exogenous antigens through fluid phase pinocytosis and receptor-mediated endocytosis and migrate to lymph nodes, where they present processed antigen to T cells. Ultraviolet B radiation impairs the antigen-presenting function of Langerhans cells, resulting in antigen-specific immunosuppression of contact hypersensitivity. We tested the notion that ultraviolet B radiation inhibits the endocytic activity of Langerhans cells, leading to impaired migration and maturation. Human monocyte-derived Langerhans cell-like dendritic cells that took up lucifer yellow or fluorescein isothiocyanate dextran exclusively migrated in response to 6Ckine/secondary lymphoid chemokine, and matured, as evidenced by an increase in CD54 and CD86 expression and potent stimulatory activity in allogeneic mixed lymphocyte reaction. Exposing Langerhans cell-like dendritic cells to 20-40 mJ per cm2 of ultraviolet B radiation reduced their endocytic activity in fluid phase pinocytosis (measured by uptake of lucifer yellow) and in receptor-mediated endocytosis (measured by uptake of fluorescein isothiocyanate dextran). Membrane ruffling and CD32 expression were also suppressed by ultraviolet B radiation. Ultraviolet B-irradiated, endocytosing Langerhans cell-like dendritic cells had less movement towards 6Ckine, expressed less CD54 and CD86, and had less effective stimulatory activity in allogeneic mixed lymphocyte reaction than nonirradiated, endocytosing Langerhans cell-like dendritic cells. Endocytosis upregulated tumor necrosis factor alpha production by Langerhans cell-like dendritic cells, but prior ultraviolet B radiation inhibited this enhancement. These data suggested that impaired endocytosis and subsequent inhibitory migration and maturation of Langerhans cells by ultraviolet B radiation could contribute to local immunosuppression of contact hypersensitivity.

Down-regulation of Toll-like receptor expression in monocyte-derived Langerhans cell-like cells: implications of low-responsiveness to bacterial components in the epidermal Langerhans cells

In the skin, there are unique dendritic cells called Langerhans cells, however, it remains unclear why this particular type of dendritic cell resides in the epidermis. Langerhans cell-like dendritic cells (LCs) can be generated from CD14 + monocytes in the presence of GM-CSF, IL-4, and TGF-β1. We compared LCs with monocyte-derived dendritic cells (DCs) generated from CD14 + monocytes in the presence of GM-CSF and IL-4 and examined the effect of exposure to two distinct bacterial stimuli via Toll-like receptors (TLRs), such as peptidoglycan (PGN) and lipopolysaccharide (LPS) on LCs and DCs. Although stimulation with both ligands induced a marked up-regulation of CD83 expression on DCs, PGN but not LPS elicited up-regulation of expression CD83 on LCs. Consistent with these results, TLR2 and TLR4 were expressed on DCs, whereas only TLR2 was weakly detected on LCs. These findings suggest the actual feature of epidermal Langerhans cells with low-responsiveness to skin commensals.

Langerhans cell-like dendritic cells in the cornea, tongue and oesophagus of the chicken (Gallus gallus).

Langerhans cells are dendritic leucocytes which reside mainly within stratified squamous epithelia of skin and mucosa. Their visualization requires the use of ATPase histochemistry, electron microscopy for identifying the unique trilaminar cytoplasmic organelles (the Langerhans cell granules or Birbeck granules), and the expression of major histocompatibility complex class II molecules. Following uptake of antigen, Langerhans cells migrate via the afferent lymphatics to the lymph nodes and undergo differentiation from an antigen-processing cell to an antigen-presenting cell. Using the same approach as that employed in previous studies for the identification of chicken epidermal Langerhans cells, we show here the presence of ATPase-positive and major histocompatibility complex class II-positive Langerhans cell-like dendritic cells at the mucosal surface of the eye, tongue and oesophagus of the chicken. Ultrastructurally, these cells qualified as Langerhans cells except that they lack Langerhans cell granules. Thus, as in mammalian skin and mucosa, chicken mucosa contains mucosal dendritic cells with morphological and phenotypical features for the engagement of incoming antigens within epithelium and lamina propria.

Engagement of the Fc epsilon RI stimulates the production of IL-16 in Langerhans cell-like dendritic cells.

Preferential uptake and presentation of IgE-bound allergens by epidermal Langerhans cells (LC) via the high affinity IgE receptor, FcepsilonRI, is regarded as an important mechanism in the induction of cutaneous inflammation in atopic dermatitis. Here, we show that activation of monocyte-derived LC-like dendritic cells (LLDC) through engagement of FcepsilonRI induces the expression of IL-16, a chemoattractant factor for dendritic cells, CD4+ T cells, and eosinophils. We found that ligation of FcepsilonRI on LLDC derived from atopic dermatitis patients that express high levels of FcepsilonRI increases IL-16 mRNA expression and storage of intracellular IL-16 protein and enhances the secretion of mature IL-16 in a biphasic manner. An early release of IL-16 (peak at 4 h) is independent of protein synthesis, while a more delayed release (peak at 12 h) requires protein synthesis and occurs subsequent to the induction of IL-16 mRNA and intracellular accumulation of pro-IL-16. There was evidence that LLDC use caspase-1 to process IL-16, as inhibition of caspase-1, but not of caspase-3, partially prevented the release of IL-16 in response to ligation of FcepsilonRI. In an in vivo model of IgE-dependent LC activation, the atopy patch test, positive skin reactions were also associated with the induction of IL-16 in epidermal dendritic cells. These data indicate that IL-16 released from LC after allergen-mediated activation through FcepsilonRI may link IgE-driven and cellular inflammatory responses in diseases such as atopic dermatitis.

Low levels of productive HIV infection in Langerhans cell-like dendritic cells differentiated in the presence of TGF-beta1 and increased viral replication with CD40 ligand-induced maturation.

Langerhans cells (LC) represent dendritic cells (DC) within mucosal epithelium that are purported initial targets for HIV following sexual exposure to virus. Here, morphologic, phenotypic, functional and HIV infection experiments were performed using monocyte-derived DC cultured in the presence of GM-CSF, IL-4 and TGF-beta1 (G4T-DC), GM-CSF and IL-4 (G4-DC), and G4T-DC incubated for an additional 3 days with CD40 ligand (CD40L-DC). G4T-DC, which demonstrated characteristics of immature LC, could be productively infected by either R5- or X4-HIV strains. Infection levels, however, were markedly lower than those observed in immature G4-DC. Surprisingly, CD40L-DC, which demonstrated features of mature LC, could be productively infected with HIV at higher levels than immature G4T-DC. Productive HIV infection in these three DC populations correlated positively with cell surface expression of CD4, CCR5 and CXCR4. We suggest that low levels of HIV infection in LC-like G4T-DC indicate an inefficient mechanism by which HIV can initially infect individuals, perhaps explaining the relative difficulty in becoming infected during sexual exposure to virus. In addition, enhanced HIV infection in LC-like G4T-DC following CD40L treatment suggests a mechanism by which inflammatory CD40L(+) T cells, if present in mucosal tissue, could lead to increased HIV transmission rates.

Leishmania major-infected murine langerhans cell-like dendritic cells from susceptible mice release IL-12 after infection and vaccinate against experimental cutaneous Leishmaniasis.

Leishmania major-infected C57BL / 6 skin-dendritic cells (DC) are activated and release cytokines (including IL-12 p70), and likely initiate protective Th1 immunity in vivo (von Stebut, E. et al., J. Exp. Med. 188: 1547 - 1552). To characterize differences in DC function in mice that are genetically susceptible (BALB / c) and resistant (C57BL / 6) to cutaneous leishmaniasis, we analyzed the effects of L. major on Langerhans cell-like, fetal skin-derived DC (FSDDC) from both strains. BALB / c- and C57BL / 6-FSDDC ingested similar numbers of amastigotes, but did not ingest metacyclic promastigotes. Like C57BL / 6-FSDDC, infection of BALB / c-FSDDC led to up-regulation of MHC class I and II antigens, CD40, CD54, and CD86 within 18 h. L. major-induced BALB / c DC activation also led to the release of TNF-alpha, IL-6 and IL-12 p40 into 18-h supernatants. Infected BALB / c- and C57BL / 6-DC both released small amounts of IL-12 p70 within 72 h. Additional stimulation with IFN-gamma and / or anti-CD40 induced the release of more IL-12 p70 from infected BALB / c-DC than C57BL / 6-DC. Co-culture of control or infected BALB / c- and C57BL / 6-DC with naive syngeneic CD4(+) T cells and soluble anti-CD3 resulted in mixed, IFN-gamma-predominant responses after restimulation with immobilized anti-CD3. Finally, syngeneic L. major-infected DC effectively vaccinated BALB / c mice against cutaneous leishmaniasis. Genetic susceptibility to L. major that results from induction of Th2 predominant immune responses after infection does not appear to reflect failure of skin DC to internalize or respond to parasites, or the inability of BALB / c T cells to mount a Th1 response to DC-associated Leishmania antigens.