Antigen-presenting Function Of Langerhans Cells Research Articles

The balance between immunity and tolerance: The role of Langerhans cells

Langerhans cells are immature skin-homing dendritic cells that furnish the epidermis with an immune surveillance system, and translate information between the internal and external milieu. Dendritic cells, in particular Langerhans cells, are gaining prominence as one of the potential principal players orchestrating the decision between immunity and tolerance. Langerhans cells capture aberrant self-antigen and pathogen-derived antigen for display to the efferent immune response. Recent evidence suggests redundancy in the antigen-presenting function of Langerhans cells, with dermal dendritic subsets capable of fulfilling an analogous role. There is mounting evidence that Langerhans cells can cross-prime T cells to recognize antigens. Langerhans cells are proposed to stimulate T regulatory cells, and are implicated in the pathogenesis of cutaneous T cell lymphoma.The phenotype of Langerhans cells, which may be tolerogenic or immunogenic, appears to depend on their state of maturity, inciting immunogen and cytokine environment, offering the potential for manipulation in immunotherapy.

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.

Differential Effects of Cytokines and Immunosuppressive Drugs on CD40, B7–1, and B7–2 Expression on Purified Epidermal Langerhans Cells

Langerhans cells are MHC class II antigen-positive antigen-presenting cells in the epidermis. Recent studies have revealed that Langerhans cells express costimulatory molecules like B7-1 and B7-2 and the accessory molecule CD40. Although these molecules are important for the antigen-presenting function of Langerhans cells, little is known about the precise regulation of their expression on purified Langerhans cells. Using a panning technique, we purified epidermal Langerhans cells to around 95% purity. Freshly prepared Langerhans cells (fLC) expressed the mRNA for receptors for M-CSF (cfms), GM-CSF (GM-CSFR), and TNF-alpha (TNFRII). TNF-alpha markedly upregulated CD40 and B7-1 expression on Langerhans cells, but not B7-2 expression. GM-CSF moderately upregulated B7-1 and B7-2 expression, and slightly upregulated CD40 expression. M-CSF moderately upregulated B7-1 expression, but did not modulate CD40 or B7-2 expression. Dexamethasone (DEX) markedly inhibited CD40, B7-1, and B7-2 expression on Langerhans cells. Cyclosporin A (CsA) and FK506 slightly inhibited CD40 and B7-1 expression on Langerhans cells, but not B7-2. Furthermore, TNF-alpha restored the DEX-induced inhibition of CD40 expression on Langerhans cells, but not the inhibition of B7-1 or B7-2 expression. GM-CSF restored DEX-induced inhibition of CD40, B7-1, and B7-2 expression. M-CSF did not affect the DEX-induced inhibition of these molecule expressions. These data provide a better understanding of the role of selective cytokines and immunosupressive drugs in the modulation of the antigen-presenting capacity of Langerhans cells.

Inhibitory effect of 1alpha,25-dihydroxyvitamin D3 on allogeneic lymphocyte stimulation and Langerhans cell maturation.

1alpha,25-Dihydroxyvitamin D3 (calcitriol) has been shown to inhibit the proliferation of peripheral blood mononuclear cells induced by allogeneic Langerhans cells in a human mixed epidermal cell lymphocyte reaction. The potent antigen-presenting function of Langerhans cells is gained during culture. We tried to dissect the effect of calcitriol on lymphocyte proliferation and Langerhans cell maturation in a murine mixed epidermal cell lymphocyte reaction using unfractioned epidermal cells as a source for Langerhans cells. First, calcitriol was added upon setup of the mixed epidermal cell lymphocyte reaction using cultured epidermal cells as antigen-presenting cells, and this was found to inhibit the proliferation of lymphocytes in a time- and concentration-dependent manner. When calcitriol was added only during preculture of freshly isolated epidermal cells, the subsequent mixed epidermal cell lymphocyte reaction was also inhibited. In addition, the growth of keratinocytes and the production of granulocyte/macrophage colony-stimulating factor during preculture of epidermal cells was completely inhibited. Supplementation with this growth factor only partially restored the proliferative response of lymphocytes. These results suggest that calcitriol inhibits both the alloantigen-driven stimulation of naive T cell and Langerhans cells maturation. Further experiments with purified Langerhans cells are required to elucidate the mechanism of action of calcitriol on Langerhans cell maturation.

UVA-induced immune suppression in human skin: protective effect of vitamin E in human epidermal cellsin vitro

UVA (320-400 nm) radiation damage to membranes, proteins, DNA and other cellular targets is predominantly related to oxidative processes. In the present study, we demonstrated that cutaneous UVA-induced immunosuppression can be related, at least in part, to the appearance of these oxidative processes. The UVA-induced oxidative processes in freshly isolated epidermal cells were monitored by measuring the thiobarbituric acid reactive substances (TBARS) as an index of peroxidation. The in vitro immunosuppressive effects of UVA were demonstrated by measuring the allogeneic lymphocyte proliferation induced by epidermal cells or purified Langerhans cells in the mixed epidermal cell-lymphocyte reaction (MECLR). In addition, the effects of a potent antioxidant (vitamin E) on these two UVA-induced processes were analysed. Our results showed that the antigen-presenting function of Langerhans cells measured in the MECLR is dose-dependently decreased by UVA radiation (up to 20J/cm2). Overnight incubation of epidermal cells with vitamin E (400 mumol/l) before irradiation partially protected epidermal cells from the immunosuppressive effects of UVA radiation, and decreased TBARS release into the supernatant (a decrease of 35% compared with a control without vitamin E). Our results suggest that UVA radiation may alter cell-presenting antigen function partly via the generation of reactive oxygen species which trigger peroxidative processes, and these data contribute to the understanding of the role of oxidative mechanisms in immune suppression induced by UVA radiation. Our in vitro model can be used to quantify UV-mediated epidermal cell damage and the degree of immune photoprotection provided by various agents.

ラット口蓋粘膜のランゲルハンス細胞の加齢的変化に関する研究

The function of Langerhans cells (LCs) is unknown for a long time. Since the antigen-presenting function of LCs was demonstrated, the study of LCs has been increased. Although the existence of LCs has been found in oral mucosa of a human being and animals, the previous researches on age change of numerical distribution and morphology of LCs are very few. In order to understand the oral immunity, the palatal mucosa of Wistar rats were used in this study from lst day to 1 year after birth. The changes of morphology and numerical distribution of LCs were observed as follows : The development of large process of LCs was found under the Hematoxylin-Eosin stain except of the slender dendritic ones. The number of LCs has reached the peak at 1 month after birth since immature LCs of palatal mucosa were found at 1st day after birth, simultaneously, the difference of numerical distribution of LCs between the hard and soft palate became more evident at 1 month after birth. Therefore, it was considered that the development and environment of oral cavity rapidly changed after weaning period. Thereafter, an increase or a decrease in number of LCs distribution was observed and a gradual decline in the numerical distribution of LCs was also shown with age as the regressive changes of oral mucosa. Thus, the role of immunological function of oral mucosa might be lower with advancing age.