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Brief communication: Long-term absence of Langerhans cells alters the gene expression profile of keratinocytes and dendritic epidermal T cells.

ABSTRACT: Tissue-resident and infiltrating immune cells are continuously exposed to molecules derived from the local cells that often come in form of secreted factors, such as cytokines. These factors are known to impact the immune cells' biology. However, very little is known about whether the tissue resident immune cells in return also affect the local environment. In this study, with the help of RNA-sequencing, we show for the first time that long-term absence of epidermal resident Langerhans cells led to significant gene expression changes in the local keratinocytes and resident dendritic epidermal T cells. Thus, immune cells might play an active role in maintaining tissue homeostasis, which should be taken in consideration at data interpretation.

SUBMITTER: Su Q

PROVIDER: S-EPMC6953782 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Brief communication: Long-term absence of Langerhans cells alters the gene expression profile of keratinocytes and dendritic epidermal T cells.

Su Qingtai Q Bouteau Aurélie A Cardenas Jacob J Uthra Balaji B Wang Yuanyaun Y Smitherman Cynthia C Gu Jinghua J Igyártó Botond Z BZ

PloS one 20200110 1

Tissue-resident and infiltrating immune cells are continuously exposed to molecules derived from the local cells that often come in form of secreted factors, such as cytokines. These factors are known to impact the immune cells' biology. However, very little is known about whether the tissue resident immune cells in return also affect the local environment. In this study, with the help of RNA-sequencing, we show for the first time that long-term absence of epidermal resident Langerhans cells led ...[more]

PMID: 31923202

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Long-term absence of Langerhans cells alters the gene expression 2 profile of keratinocytes and dendritic epidermal T cells

Project description:In this study, with the help of RNA-sequencing, we show for the first time that long-term absence of epidermal resident Langerhans cells (LCs) led to significant gene expression changes in the local keratinocytes and resident dendritic epidermal T cells

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Zinc in Keratinocytes and Langerhans Cells: Relevance to the Epidermal Homeostasis.

Project description:In the skin, the epidermis is continuously exposed to various kinds of external substances and stimuli. Therefore, epidermal barriers are crucial for providing protection, safeguarding health, and regulating water balance by maintaining skin homeostasis. Disruption of the epidermal barrier allows external substances and stimuli to invade or stimulate the epidermal cells, leading to the elicitation of skin inflammation. The major components of the epidermal barrier are the stratum corneum (SC) and tight junctions (TJs). The presence of zinc in the epidermis promotes epidermal homeostasis; hence, this study reviewed the role of zinc in the formation and function of the SC and TJs. Langerhans cells (LCs) are one of the antigen-presenting cells found in the epidermis. They form TJs with adjacent keratinocytes (KCs), capture external antigens, and induce antigen-specific immune reactions. Thus, the function of zinc in LCs was examined in this review. We also summarized the general knowledge of zinc and zinc transporters in the epidermis with updated findings.

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Long-term absence of Langerhans cells alters the gene expression 2 profile of keratinocytes and dendritic epidermal T cells

Project description:Long-term absence of Langerhans cells alters the gene expression 2 profile of keratinocytes and dendritic epidermal T cells

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Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells.

Project description:Little is known about the functional differences between the human skin myeloid dendritic cell (DC) subsets, epidermal CD207(+) Langerhans cells (LCs) and dermal CD14(+) DCs. We showed that CD14(+) DCs primed CD4(+) T cells into cells that induce naive B cells to switch isotype and become plasma cells. In contrast, LCs preferentially induced the differentiation of CD4(+) T cells secreting T helper 2 (Th2) cell cytokines and were efficient at priming and crosspriming naive CD8(+) T cells. A third DC population, CD14(-)CD207(-)CD1a(+) DC, which resides in the dermis, could activate CD8(+) T cells better than CD14(+) DCs but less efficiently than LCs. Thus, the human skin displays three DC subsets, two of which, i.e., CD14(+) DCs and LCs, display functional specializations, the preferential activation of humoral and cellular immunity, respectively.

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Project description:Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207(+) Langerhans cells (LCs) and lymphocytes that can arise in almost any tissue and cause significant morbidity and mortality. After decades of research, the cause of LCH remains speculative. A prevailing model suggests that LCH arises from malignant transformation and metastasis of epidermal LCs. In this study, CD207(+) cells and CD3(+) T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared with control epidermal CD207(+) cells, the LCH CD207(+) cells yielded 2113 differentially expressed genes (false discovery rate < 0.01). Surprisingly, the expression of many genes previously associated with LCH, including cell-cycle regulators, proinflammatory cytokines, and chemokines, were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly overexpressed in LCH CD207(+) cells. Furthermore, several genes associated with immature myeloid dendritic cells were overexpressed in LCH CD207(+) cells. Compared with the peripheral CD3(+) cells from LCH patients, the LCH lesion CD3(+) cells yielded only 162 differentially regulated genes (false discovery rate < 0.01), and the expression profile of the LCH lesion CD3(+) cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4, and SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal LCs but from accumulation of bone marrow-derived immature myeloid dendritic cells that recruit activated lymphocytes.

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Project description:Langerhans cells (LCs) constitute a subset of dendritic cells (DCs) that express the lectin langerin and that reside in their immature state in epidermis. Paradoxically, in mice permitting diphtheria toxin (DT)-mediated ablation of LCs, epidermal LCs reappeared with kinetics that lagged behind that of their putative progeny found in lymph nodes (LNs). Using bone marrow (BM) chimeras, we showed that a major fraction of the langerin(+), skin-derived DCs found in LNs originates from a developmental pathway that is independent from that of epidermal LCs. This pathway, the existence of which was unexpected, originates in the dermis and gives rise to langerin(+) dermal DCs (DDCs) that should not be confused with epidermal LCs en route to LNs. It explains that after DT treatment, some langerin(+), skin-derived DCs reappear in LNs long before LC-derived DCs. Using CD45 expression and BrdU-labeling kinetics, both LCs and langerin(+) DDCs were found to coexist in wild-type mice. Moreover, DT-mediated ablation of epidermal LCs opened otherwise filled niches and permitted repopulation of adult noninflammatory epidermis with BM-derived LCs. Our results stress that the langerin(+) DC network is more complex than originally thought and have implications for the development of transcutaneous vaccines and the improvement of humanized mouse models.

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Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions.

Project description: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 TGFbeta1 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 beta-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.

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mTORC2 Deficiency Alters the Metabolic Profile of Conventional Dendritic Cells.

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Langerhans Cells Facilitate UVB-Induced Epidermal Carcinogenesis.

Project description:UVB light is considered the major environmental inducer of human keratinocyte (KC) DNA mutations, including within the tumor-suppressor gene p53, and chronic exposure is associated with cutaneous squamous cell carcinoma formation. Langerhans cells (LCs) comprise a dendritic network within the suprabasilar epidermis, yet the role of LCs in UVB-induced carcinogenesis is largely unknown. Herein we show that LC-intact epidermis develops UVB-induced tumors more readily than LC-deficient epidermis. Although levels of epidermal cyclopyrimidine dimers following acute UVB exposure are equivalent in the presence or absence of LCs, chronic UVB-induced p53 mutant clonal islands expand more readily in association with LCs, which remain largely intact and are preferentially found in proximity to the expanding mutant KC populations. The observed LC facilitation of mutant p53 clonal expansion is completely ?? and ?? T-cell independent and is associated with increased intraepidermal expression of IL-22 and the presence of group 3 innate lymphoid cells. These data demonstrate that LCs have a key role in UVB-induced cutaneous carcinogenesis and suggest that LCs locally stimulate KC proliferation and innate immune cells that provoke tumor outgrowth.

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Project description:Cutaneous squamous cell carcinoma (SCC) is the most prevalent invasive malignancy with metastatic potential. The epidermis is exposed to a variety of environmental DNA-damaging chemicals, principal among which are polyaromatic hydrocarbons (PAHs) ubiquitous in the environment, tobacco smoke, and broiled meats. Langerhans cells (LCs) comprise a network of dendritic cells situated adjacent to basal, suprabasal, and follicular infundibular keratinocytes that when mutated can give rise to SCC, and LC-intact mice are markedly more susceptible than LC-deficient mice to chemical carcinogenesis provoked by initiation with the model PAH, 7,12-dimethylbenz[a]anthracene (DMBA). LCs rapidly internalize and accumulate DMBA as numerous membrane-independent cytoplasmic foci. Repopulation of LC-deficient mice using fetal liver LC-precursors restores DMBA-induced tumor susceptibility. LC expression of p450 enzyme CYP1B1 is required for maximal rapid induction of DNA-damage within adjacent keratinocytes and their efficient neoplastic transformation; however, effects of tumor progression also attributable to the presence of LC were revealed as CYP1B1 independent. Thus, LCs make multifaceted contributions to cutaneous carcinogenesis, including via the handling and metabolism of chemical mutagens. Such findings suggest a cooperative carcinogenesis role for myeloid-derived cells resident within cancer susceptible epithelial tissues principally by influencing early events in malignant transformation.

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