IL-10-Producing Langerhans Cells and Regulatory T Cells Are Responsible for Depressed Contact Hypersensitivity in Grafted Skin

Abstract

Although skin grafting is a common surgical technique, the immunological state of grafted skin remains unelucidated. An experimental model has shown that the development of murine contact hypersensitivity (CHS) is depressed when mice are sensitized with a hapten through full-thickness grafted skin. We explored the immunological mechanisms underlying this hyposensitization, focusing on the fate of Langerhans cells (LCs). When FITC was applied to grafted skin, FITC-bearing LCs were capable of migrating to the draining lymph nodes. Epidermal cell suspensions isolated from the grafted skin produced a high amount of IL-10 as assessed by real-time PCR. Adoptive transfer of immune lymph node cells from the sensitized mice suppressed the CHS response of recipients in an antigen-specific manner. CD4(+)CD25(+) but not CD4(+)CD25(-) T cells purified from lymph node cells were responsible for this suppression. Finally, we detected high expression of receptor activators of nuclear factor kappa-B ligand (RANKL) in the grafted skin, and found that recombinant RANKL stimulated LCs to produce IL-10. These findings suggest that the hyposensitization of CHS through the grafted skin is not attributable merely to the reduction of LC number but that IL-10-producing LCs exert a downmodulatory effect by inducing regulatory T cells.

The Mandatory Role of IL-10–Producing and OX40 Ligand-Expressing Mature Langerhans Cells in Local UVB-Induced Immunosuppression

“…Whereas murine keratinocytes are capable of releasing IL-10 (50, 52), human keratinocytes are an unlikely source of IL-10 following in vivo UVB exposure, as they express little mRNA for IL-10 and secrete no IL-10 protein (14). We have previously reported that IL-10-producing LCs in the grafted skin have a crucial role in the induction of Ag-specific Tregs (44). Together with the present finding, it is suggested that the LCs that migrate from the skin to the DLNs are the important source of IL-10 under the condition of UVB irradiation or skin grafting.…”

Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

“…In murine LC knockout models, LCs were dispensable for the development of CHS reactions (50) or even exhibited downregulatory properties (51). Induction of Tregs, as observed in different murine models of CHS (16)(17)(18) and in patients with LC histiocytosis (52), is one possibility for the tolerogenic potential of LCs. In this study, we show for the first time to our knowledge that treatment of contact-allergic patients with oral GCS endows LCs with Tregenhancing properties.…”

“…This is also true for epidermal Langerhans cells (LCs) (16)(17)(18). In mice, the interaction of the receptor activator for NF-kB (RANK) with its ligand (RANKL), originally described as regulators of bone remodeling and T cell/DC communication (19), is apparently crucial for the induction of regulatory T cells (Tregs) by LCs (17,18).…”

IL-10 controls dendritic cell–induced T-cell reactivation in the skin to limit contact hypersensitivity

“…In the skin IL-10 is produced by keratinocytes, 3 macrophages, and DCs on exposure to contact sensitizer or UV radiation. 8,9 Consequently, IL-10-deficient (IL-10 2/2 ) mice mount exaggerated T H 1 responses and exhibit increased irritant and contact hypersensitivity (CHS) reactions in the skin. 10,11 CHS is a relevant murine model for allergic contact dermatitis, one of the most common occupational diseases in human subjects.…”