IL‐34 and colony‐stimulating factor 1 (CSF1) are two alternative ligands for the CSF1 receptor that play nonredundant roles in the development, survival, and function of tissue macrophages and ...Langerhans cells (LCs). In this study, we investigated the spatio‐temporal production of IL‐34 and its impact on skin LCs in the developing embryo and adult mice in the steady state and during inflammation using Il34LacZ reporter mice and newly generated inducible Il34‐knockout mice. We found that IL‐34 is produced in the developing skin epidermis of the embryo, where it promotes the final differentiation of LC precursors. In adult life, LCs required IL‐34 to continually self‐renew in the steady state. However, during UV‐induced skin damage, LC regeneration depended on neutrophils infiltrating the skin, which produced large amounts of CSF1. We conclude that LCs require IL‐34 when residing in fully differentiated and anatomically intact skin epidermis, but rely on neutrophil‐derived CSF1 during inflammation. Our demonstration that neutrophils are an important source of CSF1 during skin inflammation may exemplify a mechanism through which neutrophils promote their subsequent replacement with mononuclear phagocytes.
Nonredundant functions of IL‐34 and CSF1 in Langerhans cells (LCs) renewal. In a fully differentiated and anatomically intact skin epidermis, keratinocytes produce IL‐34 to sustain the steady‐state renewal of LCs residing in the skin. In UV‐irradiated and inflamed skin, LC regeneration depends on CSF1 produced by infiltrating neutrophils.
Langerhans cells (LCs) are epidermis-resident antigen-presenting cells that share a common ontogeny with macrophages but function as dendritic cells (DCs). Their development, recruitment and ...retention in the epidermis is orchestrated by interactions with keratinocytes through multiple mechanisms. LC and dermal DC subsets often show functional redundancy, but LCs are required for specific types of adaptive immune responses when antigen is concentrated in the epidermis. This Review will focus on those developmental and functional properties that are unique to LCs.
Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious ...lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C‐type lectin Langerin. Both immature and mature LCs presented MV‐derived antigens in the context of HLA class II to MV‐specific CD4+ T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV‐specific CD8+ T cells. Notably, neither immature nor mature LCs were able to cross‐present exogenous UV‐inactivated MV or MV‐infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to cross‐present MV antigens, suggest that human LCs may not be directly involved in priming MV‐specific CD8+ T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8+ T‐cell priming via the endogenous antigen presentation pathway.
Langerhans' cells histiocytosis is a disease that belongs to the group of histiocytic disorders and is considered a rare pathology. It results from a proliferation and accumulation of cells of the ...phagocytic mononuclear system, including Langerhans' cells. This paper reports a case of a 4-year-old patient who presented a growing, swollen, nodular, depressible and mobile lesion in the right retroauricular region, without pain or phlogistic signs for 6 months, besides erosive and necrotic lesions in the first and second right molars. The confirmatory diagnosis was made by biopsy and immunohistochemistry. This is a study of the medical record, histological evaluations, laboratory and imaging tests of the patient, with the aim of discussing the pathology, making the diagnosis and treatment earlier.
A new langerin⁺ DC subset has recently been identified in murine dermis (langerin⁺ dDC), but the lineage and functional relationships between these cells and langerin⁺ epidermal Langerhans cells (LC) ...are incompletely characterized. Selective expression of the cell adhesion molecule EpCAM by LC allowed viable LC to be easily distinguished from langerin⁺ dDC in skin and lymphoid tissue and ex vivo as well. Differential expression of EpCAM and langerin revealed the presence of at least 3 distinct skin DC subsets. We determined that LC and langerin⁺ dDC exhibit different migratory capabilities in vitro and repopulate distinct anatomic compartments in skin at different rates after conditional depletion in vivo. Langerin⁺ dDC, in contrast to LC, did not require TGFβ1 for development. Carefully timed gene gun immunization studies designed to take advantage of the distinct repopulation kinetics of langerin⁺ dDC and LC revealed that langerin⁺ dDC were required for optimal production of β-galactosidase-specific IgG2a/c and IgG2b in the acute phase. In contrast, immunization via LC-deficient skin resulted in persistent and strikingly reduced IgG1 and enhanced IgG2a Ab production. Our data support the concepts that LC and langerin⁺ dDC represent distinct DC subsets that have specialized functions and that LC are important immunoregulatory cells. The presence of at least 3 functionally distinct skin DC subsets may have particular relevance for vaccines that are administered epicutaneously.
Langerin is a type II transmembrane C-type lectin associated with the formation of Birbeck granules in Langerhans cells. Langerin is a highly selective marker for Langerhans cells and the lesional ...cells of Langerhans cell histiocytosis. Although Langerin protein expression in Langerhans cell histiocytosis has been previously documented, the specificity of Langerin expression as determined by immunohistochemistry in the context of other histiocytic disorders has not been well established. In the present study, Langerin immunoreactivity was examined in a series of histiocytic disorders of monocyte/macrophage and dendritic cell derivation to assess the specificity and utility of Langerin as a diagnostic marker for Langerhans cell histiocytosis. Immunohistochemical expression of CD1a was also evaluated for comparison. Seventeen cases of Langerhans cell histiocytosis and 64 cases of non-Langerhans cell histiocytic disorders were examined. Langerin and CD1a were uniformly expressed in all cases of Langerhans cell histiocytosis, with the exception of one case that was positive for Langerin and negative for CD1a. Among the non-Langerhans cell histiocytic disorders evaluated, focal Langerin immunoreactivity was observed only in 2 of 10 cases of histiocytic sarcoma. All non-Langerhans cell histiocytic disorders showed no expression of CD1a. Langerin expression seems to be a highly sensitive and relatively specific marker of Langerhans cell histiocytosis. Immunohistochemical evaluation of Langerin expression may have utility in substantiating a diagnosis of Langerhans cell histiocytosis and separating this disorder from other non-Langerhans cell histiocytic proliferations.
After allergen or irritant exposure, Langerhans cells (LC) undergo phenotypic changes and exit the epidermis. In this study we describe the unique ability of MUTZ-3 derived Langerhans cells (MUTZ-LC) ...to display similar phenotypic plasticity as their primary counterparts when incorporated into a physiologically relevant full-thickness skin equivalent model (SE-LC). We describe differences and similarities in the mechanisms regulating LC migration and plasticity upon allergen or irritant exposure. The skin equivalent consisted of a reconstructed epidermis containing primary differentiated keratinocytes and CD1a+ MUTZ-LC on a primary fibroblast-populated dermis. Skin equivalents were exposed to a panel of allergens and irritants. Topical exposure to sub-toxic concentrations of allergens (nickel sulfate, resorcinol, cinnamaldehyde) and irritants (Triton X-100, SDS, Tween 80) resulted in LC migration out of the epidermis and into the dermis. Neutralizing antibody to CXCL12 blocked allergen-induced migration, whereas anti-CCL5 blocked irritant-induced migration. In contrast to allergen exposure, irritant exposure resulted in cells within the dermis becoming CD1a−/CD14+/CD68+ which is characteristic of a phenotypic switch of MUTZ-LC to a macrophage-like cell in the dermis. This phenotypic switch was blocked with anti-IL-10. Mechanisms previously identified as being involved in LC activation and migration in native human skin could thus be reproduced in the in vitro constructed skin equivalent model containing functional LC. This model therefore provides a unique and relevant research tool to study human LC biology in situ under controlled in vitro conditions, and will provide a powerful tool for hazard identification, testing novel therapeutics and identifying new drug targets.
•MUTZ-3 derived Langerhans cells integrated into skin equivalents are fully functional.•Anti-CXCL12 blocks allergen-induced MUTZ-LC migration.•Anti-CCL5 blocks irritant-induced MUTZ-LC migration.•Irritant mediated MUTZ-LC trans-differentiation to macrophage-like cell in dermis.•Trans-differentiation of MUTZ-LC is IL-10 dependent.
Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity is poorly defined. To track and discriminate LCs from dermal DCs in vivo, we developed knockin mice ...expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene. By using vital imaging, we showed that most EGFP(+) LCs were sessile under steady-state conditions, whereas skin inflammation induced LC motility and emigration to lymph nodes (LNs). After skin immunization, dermal DCs arrived in LNs first and colonized areas distinct from slower migrating LCs. LCs reaching LNs under steady-state or inflammatory conditions expressed similar levels of costimulatory molecules. Langerin and EGFP were also expressed on thymic DCs and on blood-derived, CD8alpha(+) DCs from all secondary lymphoid organs. By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization.
Antigen-Presenting Cells in the Skin Kashem, Sakeen W; Haniffa, Muzlifah; Kaplan, Daniel H
Annual review of immunology,
04/2017, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Professional antigen-presenting cells (APCs) in the skin include dendritic cells, monocytes, and macrophages. They are highly dynamic, with the capacity to enter skin from the peripheral circulation, ...patrol within tissue, and migrate through lymphatics to draining lymph nodes. Skin APCs are endowed with antigen-sensing, -processing, and -presenting machinery and play key roles in initiating, modulating, and resolving cutaneous inflammation. Skin APCs are a highly heterogeneous population with functionally specialized subsets that are developmentally imprinted and modulated by local tissue microenvironmental and inflammatory cues. This review explores recent advances that have allowed for a more accurate taxonomy of APC subsets found in both mouse and human skin. It also examines the functional specificity of individual APC subsets and their collaboration with other immune cell types that together promote adaptive T cell and regional cutaneous immune responses during homeostasis, inflammation, and disease.
PDF
