Epidermal Langerhans Cell Development and Differentiation

doi:10.1016/S0171-2985(98)80080-6

Immunobiology

Volume 198, Issue 5, March 1998, Pages 588-605

https://doi.org/10.1016/S0171-2985(98)80080-6 Get rights and content

Abstract

Epidermal Langerhans cells (LC) play a critical role in host defense. Still we know rather little about the development and functional specialization of these bone marrow-derived dendritic cells (DC) located in the most peripheral ectodermal tissue of the mammalian organism. How LC develop from their primitive progenitors in bone marrow and to what extent LC are related in their development to other lineages of the hemopoietic system is still under debate. There are currently 3 major areas of debate: 1) which are the signals required for LC development and differentiation to occur, 2) what are the (molecular) characteristics of the intermediate stages of LC differentiation, and 3) how are LC related in their development and/or function to other cells of the hemopoietic system? A better understanding of LC development and answers to these questions can be expected from recently developed technologies which allow the in vitro generation of DC with the typical molecular, morphological and functional features of LC from purified CD34⁺ progenitor cells under defined serum-free culture conditions. TGF-α1 was found to be an absolute requirement for in vitro LC development under serum-free conditions upon stimulation with the classical DC growth and differentiation factors GM-CSF, TNF-α and SCF. The recently identified cytokine FLT3 ligand further dramatically enhanced in vitro LC development and even allowed efficient in vitro generation of LC colonies from serum-free single cell cultures of CD34⁺ hemopoietic progenitor cells.

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CCL5 and CCL20 mediate immigration of Langerhans cells into the epidermis of full thickness human skin equivalents
2012, European Journal of Cell Biology
Citation Excerpt :
Several LC-precursors have been identified which are involved in the repopulation of the epidermis with LC. It has been postulated that bone marrow derived myeloid LC precursors are constantly recruited to the skin and traffic via the peripheral blood through the dermis into the epidermis (Katz et al., 1979; Strobl et al., 1998). In contrast, Merad et al. showed that bone-marrow derived precursors were not recruited to the skin during steady-state conditions and LC homeostasis was maintained by the presence of a LC precursor within the skin (Merad et al., 2002).
Epidermal Langerhans cells (LC) play a key role in initiation and regulation of immune responses. Whereas LC migration out of the epidermis upon environmental assault is extensively studied, the mechanisms involved in the (re)population of the epidermis with LC are poorly understood. Here, we investigated the immigration of LC derived from the human MUTZ-3 cell line (MUTZ-LC) into the epidermis of a full thickness skin equivalent, comprising a fully differentiated epidermis on a fibroblast-populated dermis. MUTZ-LC were used to determine which epidermis-derived chemokines play a role in mediating LC trans-dermal migration into the epidermis. We found evidence for a role of keratinocyte-derived CCL5 and CCL20 in the chemo-attraction of MUTZ-LC. Neutralizing antibodies against CCL5 and CCL20 blocked LC migration towards keratinocytes. Secretion of these two chemokines was associated with incorporation of MUTZ-LC into the epidermis of full thickness skin equivalents. In conclusion, our findings suggest that epidermis derived CCL5 and CCL20 are pivotal mediators in recruitment of LC into the epidermis.
Physiological concentrations of transforming growth factor β1 selectively inhibit human dendritic cell function
2007, International Immunopharmacology
In this study the effects of different in vitro conditioning with transforming growth factor (TGF) β1 on human monocyte-derived DC maturation (hMo-DC) were investigated. hMo-DC differentiated in the presence of physiologically relevant concentrations of TGFβ1 (2 ng/ml) failed to undergo complete maturation despite adequate stimulation with LPS or LPS + IFNγ.These hMo-DC did not produce IL-12p70 or PGE2, and showed decreased IL-10 and IL-18 production and HLA-DR expression. However, the expression of these molecules, except for IL-12p70, was not significantly affected in hMo-DC differentiated in the presence of lower concentrations of TGFβ1 (0.2 and 0.02 ng/ml). Exposure of hMo-DC to TGFβ1 (2 ng/ml) after they had completed differentiation had minimal effects. Thus, the functional response of hMo-DC to LPS or LPS + IFNγ depended on the stage of hMo-DC differentiation at which cells were first exposed to TGFβ1 and on the concentration of TGFβ1. These results suggest that in the in vivo micro-environment, the concentrations and the timing of monocyte exposure to TGFβ1 may be crucial in the differentiation of DC toward more or less mature phenotypes, and this may have important implications for DC functions. The decrease in T-cell proliferation and a small increase in IL-5 production by T cells co-cultured with hMo-DC that had been treated with TGFβ1, suggest the possibility that in vivo such DC may provide chronic, but incomplete signals to T cells, and this could be a potential mechanism underlying polarisation of T cells towards anergy.
Human CD34+CD11b- cord blood stem cells generate in vitro a CD34-CD11b+ subset that is enriched in langerin+ Langerhans dendritic cell precursors
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We investigated whether the expression of CD11b on precursors derived in vitro from CD34⁺ hematopoietic stem cells was related to their ability to generate CD11b⁻ and CD11b⁺ Langerhans dendritic cells (LC).
Human CD34⁺ cells purified from cord blood were cultured with FLT3 ligand, thrombopoietin, and stem cell factor (FTS) for 2 weeks, analyzed, and sorted by FACS. Sorted fractions were cultured as above, or differentiated into LC with GM-CSF, IL-4, and TGF-β1 (G4-TGF) for 6 days. The capacity of LC to internalize langerin and dextran was assessed.
Ex vivo, human CD34⁺ cells were CD11b⁻ and mostly CLA⁺. After 2 weeks of culture with FTS, CD34⁻CLA⁻CD11b⁻ and CD34⁻CLA⁻CD11b⁺ cells emerged. CD11b⁻ cells were the most ancestral because they were the only ones to proliferate with FTS, and constantly generated CD11b⁺ cells. Both CD11b⁻ and CD11b⁺ sorted cells generated E-cadherin⁺langerin⁺ LC after incubation with G4-TGF. The former fraction contained 46% ± 15% of E-cadherin⁺ and 10% ± 5% of langerin⁺ cells, whereas in the latter fraction these values reached respectively 66% ± 23% and 30% ± 16% (mean ± SD, n = 7, p < 0.056). Looking at functional properties, CD11b⁻ and CD11b⁺ LC were similar in terms of langerin and dextran endocytosis. By contrast, only CD11b⁺ LC internalized fluorescent LPS.
Human CD34⁺CD11b⁻ cells differentiate in FTS culture into a CD34⁻CD11b⁻ precursor that in turn generates CD34⁻CD11b⁺ cells. These cells are enriched in LC precursors compared to CD34⁻CD11b⁻ cells. Both CD11b⁻ and CD11b⁺ LC are generated in vitro, and each fraction may assume different functions in inflammatory situations.
CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM)
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Herpes simplex virus (HSV)-associated erythema multiforme (HAEM) is a recurrent disease characterized by the presence and expression of HSV DNA fragments in lesional skin. Our studies examined the mechanism of viral DNA transport to the skin of HAEM patients. CD34+ cells were isolated from the blood of normal subjects and HSV and HAEM patients during acute lesions and at quiescence. They were cultured with cytokines that favor their differentiation into Langerhans cells (LC) precursors (CD1a+/CD14-) and examined for HSV replication, HSV-induced cellular alterations, viral DNA fragmentation, and clearance. CD34+ cells from all study groups were non-permissive for HSV replication but infection favored their differentiation into CD1a+/CD14- LC precursors and upregulated E-cadherin expression, thereby assisting LC targeting to the skin. Only HAEM patients had CD34+ cells that retained viral DNA fragments, notably polymerase DNA, for at least 7 d of in vitro culture. The percentages of circulating CD34+ (and CD34+/CLA+) cells were significantly higher in HAEM patients at the time of acute lesions. A similar increase was not seen for HSV patients. The data are the first report implicating CD34+ cells in HAEM pathogenesis, likely by transporting HSV DNA fragments to lesional skin.
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^a: Walter Knapp, M.D., Institute of Immunology, University of Vienna, Borschkegasse 8a, A - 1090 Vienna, AUSTRIA.

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Epidermal Langerhans Cell Development and Differentiation

Abstract

J. Invest. Derm.

J. Invest. Dermatol.

J. Invest. Derm.

Immunology Today

J. Invest. Dermatol.

Blood

Blood

Blood

Blood

Blood

Immunity

Blood

Blood

Blood

Lancet

Immunol. Lett.

Blood

Trends in Cell Biol.

Blood

Blood

Blood

Blood

Cell

Blood

Cell

Blood

Blood

The dendritic cell system and its role in immunogenicity

Annu. Rev. Immunol.

Über die Nerven der menschlichen Haut

Virchows Arch. Pathol. Anat. Physiol.

The skin: initiation and target site of immune responses

Recent Results Cancer Res.

The Langerhans Cell

Curt. Probl. Derm.

Epidermal Langerhans cells bear Fc and C3 receptors

Nature

Immunologicl functions of Ia-bearing epidermal Langerhans cells

J. Immunol.

Reactivity of Langerhans cells with hybridoma antibody

Proc. Natl. Acad. Sci. USA

Calcium-dependent cell-cell adhesion molecules common to hepatocytes and teratocarcinoma stem cells

J. Cell Biol.

Human epidermal Langerhans cells express only the 40-kilodalton Fcγ Receptor (FcRII)

J. Immunol.

Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin

Nature

Epidermal Langerhans cells are derived from cells originating in the bone marrow

Nature

Cytogenetic identification of allogeneic epidermal Langerhans cells in a bone marrow-graft recipient

N. Eng. J. Med.

Human dendritic cells and macrophages

Am. J. Pathol.

GM-CSF and TNF-a cooperate in the generation of dendritic Langerhans cells

Nature

Immunohistological Analysis of human mononuclear phagocytes and dendritic cells by using monoclonal antibodies

Lab. Invest.

Phagocytosis of antigens by Langerhans cells in vitro

J. Exp. Med.

Experimental cutaneous leishmaniasis: Langerhans cells internalize Leishmania major and induce an antigen-specific T-cell response

Adv. Exp. Biol.

Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow

J. Immunol.

TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages

J. Leukoc. Biol.

Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha

J. Exp. Med.

Generation of antigen-presenting cells for soluble protein antigens ex vivo from peripheral blood CD34+ hematopoietic progenitor cells in cancer patients

Eur. J. Immunol.

TGF-β1 promotes in vitro development of dendritic cells from CD34+ hemopoietic progenitors

J. Immunol.

Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34⁺ progenitors in human bone marrow

Identification of dendritic cell colony-forming units among normal human CD34⁺ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha

Generation of antigen-presenting cells for soluble protein antigens ex vivo from peripheral blood CD34⁺ hematopoietic progenitor cells in cancer patients

TGF-β1 promotes in vitro development of dendritic cells from CD34⁺ hemopoietic progenitors