Migration Of Langerhans Cells Research Articles

Oral administration of paeoniflorin attenuates allergic contact dermatitis by inhibiting dendritic cell migration and Th1 and Th17 differentiation in a mouse model.

Allergic contact dermatitis (ACD) is a hapten-specific CD4(+) T-cells mediated inflammatory response of the skin. Its pathomechanism involves 2 phases, an induction phase and an elicitation phase. Langerhans cells (LCs) and dendritic cells (DCs) in the skin play key roles in presenting low molecular weight chemicals (haptens) to the lymph nodes. Therefore, inhibition of the migration of LCs or DCs and T-cell proliferation is each expected to control ACD disease. To explore the effectiveness of paeoniflorin (PF) on the migration of LCs and T-cell proliferation in vivo, we establish a murine model of ACD, promoted by repeated exposure to an allergen (specifically 1-Chloro-2,4-dinitrobenzene (DNCB)). Administration of PF inhibits DC migration in this DNCB-induced model in the induction phase. As a result, epidermal LC density in the elicitation phase increased in PF-treated mice when compared to PF-untreated mice. At the same time, PF reduced IFN-γ(+)CD4(+) and IL-17(+)CD4(+) T cells proliferation (but not IL-4(+)CD4(+) T cells proliferation), leading to an attenuated cutaneous inflammatory response. Consistent with this T-cell proliferation profile, secretions of IFN-γ and IL-17 were reduced and IL-10 secretion increased in PF-treated mice, but production of IL-4 and IL-5 remained unchanged in the skin and blood samples. These results suggest that oral administration of PF can treat and prevent ACD effectively through inhibition of DC migration, and thus decrease the capacity of DCs to stimulate Th1 and Th17 cell differentiation and cytokine production.

Gingiva Equivalents Secrete Negligible Amounts of Key Chemokines Involved in Langerhans Cell Migration Compared to Skin Equivalents.

Both oral mucosa and skin have the capacity to maintain immune homeostasis or regulate immune responses upon environmental assault. Whereas much is known about key innate immune events in skin, little is known about oral mucosa. Comparative studies are limited due to the scarce supply of oral mucosa for ex vivo studies. Therefore, we used organotypic tissue equivalents (reconstructed epithelium on fibroblast-populated collagen hydrogel) to study cross talk between cells. Oral mucosa and skin equivalents were compared regarding secretion of cytokines and chemokines involved in LC migration and general inflammation. Basal secretion, representative of homeostasis, and also secretion after stimulation with TNFα, an allergen (cinnamaldehyde), or an irritant (SDS) were assessed. We found that proinflammatory IL-18 and chemokines CCL2, CCL20, and CXCL12, all involved in LC migration, were predominantly secreted by skin as compared to gingiva. Furthermore, CCL27 was predominantly secreted by skin whereas CCL28 was predominantly secreted by gingiva. In contrast, general inflammatory cytokines IL-6 and CXCL8 were secreted similarly by skin and gingiva. These results indicate that the cytokines and chemokines triggering innate immunity and LC migration are different in skin and gingiva. This differential regulation should be figured into novel therapy or vaccination strategies in the context of skin versus mucosa.

Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis.

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK–DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non–high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.

Skin sensitization induced Langerhans’ cell mobilization: variable requirements for tumour necrosis factor‐α

Upon antigen/allergen recognition, epidermal Langerhans' cells (LC) are mobilized and migrate to the local lymph node where they play a major role in initiating or regulating immune responses. It had been proposed that all chemical allergens induce LC migration via common cytokine signals delivered by TNF-α and IL-1β. Here the dependence of LC migration on TNF-α following treatment of mice with various chemical allergens has been investigated. It was found that under standard conditions the allergens oxazolone, paraphenylene diamine, and trimellitic anhydride, in addition to the skin irritant sodium lauryl sulfate, were unable to trigger LC mobilization in the absence of TNF-α signalling. In contrast, two members of the dinitrohalobenezene family (2,4-dinitrochlorobenzene [DNCB] and 2,4-dinitrofluorobenzene [DNFB]) promoted LC migration independently of TNF-R2 (the sole TNF-α receptor expressed by LC) and TNF-α although the presence of IL-1β was still required. However, increasing doses of oxazolone overcame the requirement of TNF-α for LC mobilization, whereas lower doses of DNCB were still able to induce LC migration in a TNF-α-independent manner. These novel findings demonstrate unexpected heterogeneity among chemical allergens and furthermore that LC can be induced to migrate from the epidermis via different mechanisms that are either dependent or independent of TNF-α. Although the exact mechanisms with regard to the signals that activate LC have yet to be elucidated, these differences may translate into functional speciation that will likely impact on the extent and quality of allergic sensitization.

Intradermal Vaccination against SIV Induces the Activation and Migration of Langerhans Cells in Non-human Primates

AIDS Research and Human RetrovirusesVol. 30, No. S1 AdjuvantsIntradermal Vaccination against SIV Induces the Activation and Migration of Langerhans Cells in Non-human PrimatesLucille Adam, Biliana Todorova, Roger Le Grand, Catherine Chapon, and Frederic MartinonLucille AdamCEA, Division of Immuno-Virology, IDMIT Center, Fontenay aux Roses, FranceUniversité Paris-Sud, UMR E1, Orsay, FranceVaccine Research Institute (VRI), Créteil, FranceSearch for more papers by this author, Biliana TodorovaCEA, Division of Immuno-Virology, IDMIT Center, Fontenay aux Roses, FranceUniversité Paris-Sud, UMR E1, Orsay, FranceVaccine Research Institute (VRI), Créteil, FranceSearch for more papers by this author, Roger Le GrandCEA, Division of Immuno-Virology, IDMIT Center, Fontenay aux Roses, FranceUniversité Paris-Sud, UMR E1, Orsay, FranceVaccine Research Institute (VRI), Créteil, FranceSearch for more papers by this author, Catherine ChaponCEA, Division of Immuno-Virology, IDMIT Center, Fontenay aux Roses, FranceUniversité Paris-Sud, UMR E1, Orsay, FranceVaccine Research Institute (VRI), Créteil, FranceSearch for more papers by this author, and Frederic MartinonCEA, Division of Immuno-Virology, IDMIT Center, Fontenay aux Roses, FranceUniversité Paris-Sud, UMR E1, Orsay, FranceVaccine Research Institute (VRI), Créteil, FranceSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5417.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Intradermal Vaccination against SIV Induces the Activation and Migration of Langerhans Cells in Non-human Primates." AIDS Research and Human Retroviruses, 30(S1), p. A194FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Lucille Adam, Biliana Todorova, Roger Le Grand, Catherine Chapon, and Frederic Martinon.Intradermal Vaccination against SIV Induces the Activation and Migration of Langerhans Cells in Non-human Primates.AIDS Research and Human Retroviruses.Oct 2014.A194-A194.http://doi.org/10.1089/aid.2014.5417.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Topical pimecrolimus inhibits high-dose UVB irradiation-induced epidermal Langerhans cell migration, via regulation of TNF-α and E-cadherin.

BackgroundTopical pimecrolimus has been shown to reverse epidermal CD1a+ Langerhans cell reduction induced by high-dose ultraviolet (UV)B irradiation, but the mechanism is still unclear. This study aimed to investigate the possible mechanism of the effect of pimecrolimus on high-dose UVB-irradiated epidermal Langerhans cells.MethodsForty human foreskin tissues were divided into four groups: control; pimecrolimus-only; UVB-only; and UVB + pimecrolimus. All tissues were cultured, and each tissue was cut into four pieces, corresponding to four time points (0 hours, 18 hours, 24 hours, and 48 hours). We collected the tissues and culture medium at each time point. The percentage of CD1a+ cells in medium was detected by flow cytometry. The tissues were detected for messenger (m)RNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and E-cadherin, by reverse-transcription polymerase chain reaction (PCR) and Western blot.ResultsAt 18 hours, 24 hours, and 48 hours, the CD1a+ cells in the culture medium of the UVB-only group and the UVB + pimecrolimus group were significantly more than in the control group, while the CD1a+ cells of the UVB + pimecrolimus group was less than of the UVB-only group. For both the UVB-only group and UVB + pimecrolimus group, TNF-α expression (by both reverse-transcription PCR and Western blot) of the tissues was clearly higher and E-cadherin expression was significantly lower compared with the control group, at 18 hours, 24 hours, and 48 hours. For the UVB + pimecrolimus group, TNF-α was clearly lower and E-cadherin was significantly higher compared with the UVB-only group.ConclusionTopical pimecrolimus inhibited epidermal Langerhans cell migration induced by high-dose UVB irradiation, via regulation of TNF-α and E-cadherin.

Macrophage- and neutrophil-derived TNF-α instructs skin langerhans cells to prime antiviral immune responses.

Dendritic cells are major APCs that can efficiently prime immune responses. However, the roles of skin-resident Langerhans cells (LCs) in eliciting immune responses have not been fully understood. In this study, we demonstrate for the first time, to our knowledge, that LCs in cynomolgus macaque skin are capable of inducing antiviral-specific immune responses in vivo. Targeting HIV-Gag or influenza hemagglutinin Ags to skin LCs using recombinant fusion proteins of anti-Langerin Ab and Ags resulted in the induction of the viral Ag-specific responses. We further demonstrated that such Ag-specific immune responses elicited by skin LCs were greatly enhanced by TLR ligands, polyriboinosinic polyribocytidylic acid, and R848. These enhancements were not due to the direct actions of TLR ligands on LCs, but mainly dependent on TNF-α secreted from macrophages and neutrophils recruited to local tissues. Skin LC activation and migration out of the epidermis are associated with macrophage and neutrophil infiltration into the tissues. More importantly, blocking TNF-α abrogated the activation and migration of skin LCs. This study highlights that the cross-talk between innate immune cells in local tissues is an important component for the establishment of adaptive immunity. Understanding the importance of local immune networks will help us to design new and effective vaccines against microbial pathogens.

Guttate psoriasis is associated with an intermediate phenotype of impaired Langerhans cell migration

An episode of guttate psoriasis can be an isolated event, can recur as guttate episodes, or develop into chronic plaque psoriasis (CPP). A previous study revealed that early-onset (before age 40 years) CPP is associated with inhibition of epidermal Langerhans cell (LC) migration. To determine whether guttate psoriasis is also associated with abnormal LC mobilization. Three groups of patients were recruited: current guttate episode (n = 5); guttate psoriasis progressed to CPP (n = 6); and resolved guttate psoriasis (n = 2). Biopsies were taken from uninvolved skin and LC migration was measured ex vivo using an epidermal explant model. Patients with a current episode of guttate psoriasis displayed epidermal LC migration, although the extent was significantly lower than in skin from healthy controls (P < 0·05). In contrast, in those patients in whom guttate psoriasis developed into CPP there was no mobilization of LC. Finally, in patients in whom guttate psoriasis had resolved, LC migration was normal. We have shown that guttate psoriasis is associated with an abnormality of LC mobilization, but a less marked inhibition compared with that seen in CPP. In resolved guttate psoriasis LC function returns to normal. These data provide further evidence that the pathogenesis of psoriasis is characterized by significant changes in epidermal LC function.

Increased lymph node CD8+ T cell proliferation and memory cell markers upon conditional ablation of Langerhans cells in autoimmune mice (BA14P.215)

Abstract Systemic autoimmune diseases such as lupus are characterized by inflammation in many organs. The role of local tissue-resident immune cells in specific organ involvement in these diseases remains unclear. We evaluated the role of Langerhans cells (LC) as prototypic tissue-resident dendritic cells (DC) in eliciting local immune defects in the MRL model of lupus. Injection of diphtheria toxin (DT) in Lang-eGFP.DTR knock-in mice results in depletion of langerin+ dermal DC (dDC) and LC. To assess LC’s role in systemic autoimmunity, we introgressed the knock-in mutation from the stock B6 onto the MRL background. Serial DT injections every 7-10 days exacerbate inflammation in the skin (King et al) and cornea in MRL but not in B6 mice. To investigate underlying mechanisms, we assessed the effect of LC depletion on T cells in skin/eye draining cervical lymph nodes (cLN). There was a significantly higher proliferation of CD8+, but not CD4+, T cells in cLN of LC-ablated than control mice; such effect was not seen in spleen CD8+ T cells. Also, LC-ablated MRL, but not B6 mice, exhibited reduced CD62L on cLN T cells. Further, freshly isolated dDC were more efficient than LC in promoting the proliferation of CD8+, but not CD4+, cNL T cells. Such local regulation of CD8+ T cells may play a role in immune tolerance locally. A defect in this mechanism owing to reduced LC migration in MRL mice (Eriksson and Singh, 2008) may confer skin/eye inflammation, without affecting other organs

The XS106 cell: a Langerhans’ cell surrogate with a selective type 2 phenotype

Epidermal Langerhans’ cells (LC) play important roles in initiating and regulating cutaneous immune responses. However, LC comprise less than 3% of all epidermal cells and consequently are difficult to study ex vivo. In the current investigations, we have examined the utility of the XS106 cell line, a dendritic cell (DC) line derived from mouse epidermis, as a surrogate for LC. Membrane marker expression, type 1- and type 2-associated chemokine production, and migration patterns have been characterised following treatment of XS106 cells with a range of toll-like receptor (TLR) ligands. Comparisons have been made with mouse bone marrow-derived DC- and LC-derived ex vivo. Like BMDC, XS106 cells expressed generic DC markers, in addition to displaying higher levels of skin DC markers compared with BMDC. XS106 cells and LC-enriched epidermal fractions both displayed higher constitutive expression of type 2-associated chemokines than type 1 chemokines. Furthermore, although treatment with a range of TLR ligands induced cytokine secretion by XS106 cells, only type 2 TLR ligands increased membrane marker expression of major histocompatibility complex class II and co-stimulatory molecules. Moreover, type 1-associated TLR ligands failed to induce selective type 1 chemokine secretion by XS106 cells. XS106 cells also displayed functional similarity to LC, migrating in response to chemokines that are known to induce the migration of LC. On the basis of membrane marker expression and selective type 2 polarisation XS106 cells provide a useful surrogate for LC.

Suppression of Langerhans cell activation is conserved amongst human papillomavirus α and β genotypes, but not a µ genotype

Human papillomavirus (HPV) has evolved mechanisms that allow it to evade the human immune system. Studies have shown HPV-mediated suppression of activation of Langerhans cells (LC) is a key mechanism through which HPV16 evades initial immune surveillance. However, it has not been established whether high- and low-risk mucosal and cutaneous HPV genotypes share a common mechanism of immune suppression. Here, we demonstrate that LC exposed to capsids of HPV types 18, 31, 45, 11, (alpha-papillomaviruses) and HPV5 (beta-papillomavirus) similarly suppress LC activation, including lack of costimulatory molecule expression, lack of cytokine and chemokine secretion, lack of migration, and deregulated cellular signaling. In contrast, HPV1 (mu-papillomavirus) induced costimulatory molecule and cytokine upregulation, but LC migration and cellular signaling was suppressed. These results suggest that alpha and beta HPV genotypes, and partially a mu genotype, share a conserved mechanism of immune escape that enables these viruses to remain undetected in the absence of other inflammatory events.

Skin as a Novel Route for Allergen-specific Immunotherapy

Subcutaneous allergen specific immunotherapy is an effective treatment of IgE-mediated allergies, but it requires repeated allergen injections with a risk of systemic allergic reactions. Other routes of immunization had been explored to improve patient compliance and safety. Skin is not only a physical barrier between the body and outside world, but also an important immune organ eliciting innate and adaptive immune function. Skin has been used as an ideal site for vaccination of infectious diseases. Food allergen topically applied onto disrupted skin can induce sensitization and food allergy would develop subsequently. However, immune tolerance would be induced if the skin barrier is kept intact. Several mice and human studies on epicutaneous immunotherapy showed successful treatment on IgE-induced allergy models or allergic diseases. Migratory Langerhans cells might play a decisive role in the induction of different immune responses. Further research on the underlying mechanism of the crosstalk between skin and gut or airway is helpful for the understanding of many protective or sensitizing immune responses induced via skin, and also is helpful for the development of new strategy for the treatment of allergic disease.

Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion

LIM-kinases (LIMKs) play crucial roles in various cell activities, including migration, division, and morphogenesis, by phosphorylating and inactivating cofilin. Using a bimolecular fluorescence complementation assay to detect the actin-cofilin interaction, we screened LIMK1 inhibitors and identified two effective inhibitors, damnacanthal (Dam) and MO-26 (a pyrazolopyrimidine derivative). These compounds have already been shown to inhibit Lck, a Src family tyrosine kinase. However, in vitro kinase assays revealed that Dam inhibited LIMK1 more effectively than Lck. Dam suppressed LIMK1-induced cofilin phosphorylation and deceleration of actin retrograde flow in lamellipodia in N1E-115 cells. Dam impaired CXCL12-induced chemotactic migration of Jurkat T lymphocytes and Jurkat-derived, Lck-deficient JCaM1.6 cells and also inhibited serum-induced migration and invasion of MDA-MB-231 breast carcinoma cells. These results suggest that Dam has the potential to suppress cell migration and invasion primarily through the inhibition of LIMK kinase activity. Topical application of Dam also suppressed hapten-induced migration of epidermal Langerhans cells in mouse ears. Dam provides a useful tool for investigating cellular and physiological functions of LIMKs and holds promise for the development of agents against LIMK-related diseases. The bimolecular fluorescence complementation assay system used in this study will provide a useful method to screen for inhibitors of various protein kinases.

Early events after skin injury: Observations on changes in Langerhans cells and Birbeck granules with role of phosphorylase kinase in the injury pathway

Background and Aim: To evaluate the role of Langerhans cells (LCs) in the early events of the injury pathway, we studied activated and unactivated LCs in sequential biopsies from uninvolved skin of psoriatic and nonpsoriatic individuals using immunocytochemistry and electron microscopy. Methods: Tape-stripping injury was used for cell activation. Changes suggestive of LC activation were observed as early as 5-30 min following tape-stripping. These consisted of abundant Golgi cisternae, proliferation of rough endoplasmic reticulum consistent with increased protein synthesis, increased folds and waviness of the nuclear membranes, and development of migratory status as shown by shortening of dendritic processes and presence of spaces around the LCs from detachment of the cell-membranes from the adjacent keratinocytes. Results: There were notable changes in Birbeck granules (BGs) in LCs, with an inverse correlation of BG density with cell activation as early as 5 min after tape-stripping. The BG was most abundant in the unactivated LCs, and least numerous after activation. With cell activation, BG was observed to be few and unstacked, with isolated granules opening to the cell surface. The presence of T6 antigen (CD1a) 30 min after tape-stripping, with loss of epidermal T6+ LCs and presence of T6+ LCs within the dermal blood vessels 24 h after tape-stripping, strongly suggest development of LCs' migratory status, followed by amplification of the immune response 7 days after tape-stripping. Conclusion: Because BG contain both C-type lectin (langerin) and T6 antigen (CD1a), BG in activated LCs may provide a mechanism whereby presynthesized molecules (langerin, T6/CD1a, toll receptors) necessary for early LC activation and migration may be simultaneously delivered to the cell surface membrane for rapid enhancement of activated cell function by nonpeptide antigens.

Tumor-promoting role of TGFβ1 signaling in ultraviolet B-induced skin carcinogenesis is associated with cutaneous inflammation and lymph node migration of dermal dendritic cells

Transforming growth factor beta 1 (TGFβ1) is a pleiotropic cytokine in the skin that can function both as a tumor promoter and suppressor in chemically induced skin carcinogenesis, but the function in ultraviolet B (UVB) carcinogenesis is not well understood. Treatment of SKH1 hairless mice with the activin-like kinase 5 (ALK5) inhibitor SB431542 to block UVB-induced activation of cutaneous TGFβ1 signaling suppressed skin tumor formation but did not alter tumor size or tumor cell proliferation. Tumors that arose in SB-treated mice after 30 weeks had significantly reduced percentage of IFNγ(+) tumor-infiltrating lymphocytes compared with control mice. SB431542 blocked acute and chronic UVB-induced skin inflammation and T-cell activation in the skin-draining lymph node (SDLN) and skin but did not alter UVB-induced epidermal proliferation. We tested the effect of SB431542 on migration of skin dendritic cell (DC) populations because DCs are critical mediators of T-cell activation and cutaneous inflammation. SB431542 blocked (i) UVB-induced Smad2 phosphorylation in dermal DC (dDC) and (ii) SDLN and ear explant migration of CD103(+) CD207(+) and CD207(-) skin DC subsets but did not affect basal or UV-induced migration of Langerhans cells. Mice expressing a dominant-negative TGFβ type II receptor in CD11c(+) cells had reduced basal and UVB-induced SDLN migration of CD103(+) CD207(+) and CD207(-) DC subsets and a reduced percentage of CD86(high) dDC following UVB irradiation. Together, these suggest that TGFβ1 signaling has a tumor-promoting role in UVB-induced skin carcinogenesis and this is mediated in part through its role in UVB-induced migration of dDC and cutaneous inflammation.

Langerhans cell maturation is accompanied by induction of N‐cadherin and the transcriptional regulators of epithelial–mesenchymal transition ZEB1/2

Langerhans cells (LCs) are a unique subset of dendritic cells (DCs) that express epithelial adhesion molecules, allowing them to form contacts with epithelial cells and reside in epidermal/epithelial tissues. The dynamic regulation of epithelial adhesion plays a decisive role in the life cycle of LCs. It controls whether LCs remain immature and sessile within the epidermis or mature and egress to initiate immune responses. So far, the molecular machinery regulating epithelial adhesion molecules during LC maturation remains elusive. Here, we generated pure populations of immature human LCs in vitro to systematically probe for gene-expression changes during LC maturation. LCs down-regulate a set of epithelial genes including E-cadherin, while they upregulate the mesenchymal marker N-cadherin known to facilitate cell migration. In addition, N-cadherin is constitutively expressed by monocyte-derived DCs known to exhibit characteristics of both inflammatory-type and interstitial/dermal DCs. Moreover, the transcription factors ZEB1 and ZEB2 (ZEB is zinc-finger E-box-binding homeobox) are upregulated in migratory LCs. ZEB1 and ZEB2 have been shown to induce epithelial-to-mesenchymal transition (EMT) and invasive behavior in cancer cells undergoing metastasis. Our results provide the first hint that the molecular EMT machinery might facilitate LC mobilization. Moreover, our study suggests that N-cadherin plays a role during DC migration.

MicroRNA miR-17-92 cluster is highly expressed in epidermal Langerhans cells but not required for its development

Langerhans cells (LCs) are bone marrow-derived immature skin-residential dendritic cells (DCs) with a life cycle distinct from that of other types of DCs. The mechanisms involved in LC homeostasis and immunological functions are still not clear. MicroRNAs (miRNAs) are a class of short noncoding RNAs that regulate gene expression through either translational repression or mRNA degradation. A recent study showed that specific deletion of total miRNAs in DCs affects the homeostasis and function of only LCs, but not of other types of DCs. The roles of specific individual miRNA in LC development are still lacking. The miRNA miR-17-92 class, encoding miR-17, miR-18, miR-19a, miR-19b, miR-20 and miR-92, plays a very important role in B- and T-cell development and function. Here, we first report that epidermal LCs highly express the miR-17-92 class compared with spleen naive T cells. To further characterize the role of miR-17-92 in LC development, we generated LC-specific miR-17-92 knockout and knock-in mice. Interestingly, LC-specific gain- and loss-of-function of miR-17-92 cluster did not significantly change LC homeostasis, maturation ability, antigen capture and migration to draining lymph nodes. Thus, the miR-17-92 cluster may be functionally redundant and not critically required for LC development and function.

A Unique Dermal Dendritic Cell Subset That Skews the Immune Response toward Th2

Dendritic cell (DC) subsets in the skin and draining lymph nodes (LNs) are likely to elicit distinct immune response types. In skin and skin-draining LNs, a dermal DC subset expressing macrophage galactose-type C-type lectin 2 (MGL2/CD301b) was found distinct from migratory Langerhans cells (LCs) or CD103+ dermal DCs (dDCs). Lower expression levels of Th1-promoting and/or cross-presentation-related molecules were suggested by the transcriptome analysis and verified by the quantitative real-time PCR analysis in MGL2+ dDCs than in CD103+ dDCs. Transfer of MGL2+ dDCs but not CD103+ dDCs from FITC-sensitized mice induced a Th2-type immune response in vivo in a model of contact hypersensitivity. Targeting MGL2+ dDCs with a rat monoclonal antibody against MGL2 efficiently induced a humoral immune response with Th2-type properties, as determined by the antibody subclass. We propose that the properties of MGL2+ dDCs, are complementary to those of CD103+ dDCs and skew the immune response toward a Th2-type response.

Multifocal Extradural and Intradural Eosinophilic Granuloma

Eosinophilic granuloma is a type of histiocytosis X that is a benign bone tumor. Multifocal extradural and intradural involvement in adults is extremely uncommon because 90% of cases occur in boys younger than 10 years. The etiology of this disease is unknown, but it occurs with the accumulation of eosinophils and histiocytes in the medullary layers of the bone. The beginning of the inflammatory process in the dural membrane after migration of Langerhans cells may result in intradural involvement and sinus invasion into the nearby tissue. For multiple bone lesions, the use of chemotherapy, radiotherapy, and systematic cortisone is effective. In this study, we discuss the case of a 44-year-old man with sinus compression and multiple painful cranial swellings who was admitted to our clinic.

Conditional ablation of Langerhans cells exacerbates autoimmune corneal inflammation (P5134)

Abstract Ocular surface inflammation is common and sometimes severe in autoimmune diseases. Little is known about the role of cornea-resident dendritic cells, including Langerhans cells (LC), in ocular surface autoimmunity. Here, we analyzed corneal LC in autoimmune-prone MRL mice. LC (CD11c+ CD207+) were more abundant and activated (CD86+ CD40+) in the corneal epithelium of MRL mice than of B6 mice. However, LC were ~5-fold lower in the corneal stroma of MRL mice than of B6 mice. LC in cervical lymph nodes were also lower in MRL mice than in B6 mice. Ongoing studies will examine whether the increase of activated LC in corneal epithelium, but their reduction in corneal stroma and eye-draining lymph nodes in autoimmune mice is due to a defect in the migration of LC from the cornea to eye-draining lymph nodes. Since LC are believed to carry antigens from tissues to their respective draining lymph nodes to maintain tolerance in a tissue-specific manner, the reduced LC in eye-draining lymph nodes may lead to the breakdown of tolerance to eye antigens. To directly test the role of LC in ocular autoimmunity, we introgressed the Lang-eGFP.DTR knockin mutation from the stock B6 mice that express diphtheria toxin receptor (DTR) driven by Langerin promoter (Malissen, 2005) onto the MRL background. Diphtheria toxin injections depleted LC in Lang-eGFP.DTR MRL mice and accelerated corneal inflammation. Taken together, these data suggest a protective role of LC in corneal inflammation.