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

Abstract

Although glucocorticosteroids (GCSs) have been used for many decades in transplantation and (auto)inflammatory diseases, the exact mechanisms responsible for their immunosuppressive properties are not fully understood. The purpose of this study was to characterize the effects of oral GCSs on the cutaneous immune response. We analyzed, by immunofluorescence staining and quantitative RT-PCR, residual skin biopsy material from a clinical study in which we had used oral GCS as positive control for determining the effects of candidate anti-inflammatory compounds on epicutaneous patch tests of Ni-allergic patients. Expectedly, oral GCS treatment led to a reduction of clinical symptoms and infiltrating leukocytes. Notably, we observed increased numbers of dermal FOXP3+CD25+ T cells and epidermal Langerhans cells (LCs) that were associated with upregulated mRNA expression of TGF-β in lesions of GCS-treated Ni-allergic patients. To investigate this phenomenon further, we exposed purified LCs to GCS. They exhibited, in contrast to GCS-nonexposed LCs, 1) a more immature phenotype, 2) higher intracellular amounts of TGF-β, and 3) increased receptor activator for NF-κB expression, conditions that reportedly favor the expansion of regulatory T cells (Tregs). Indeed, we observed an enhancement of functionally suppressive FOXP3+ T cells when CD3+ cells were incubated with GCS-pretreated LCs. The expansion of Tregs was inhibited by TGF-β blockage alone, and their suppressive activity was neutralized by a combination of anti–TGF-β and anti–IL-10 Abs. Our data show that systemically applied GCSs endow LCs with Treg-promoting properties and thus shed new light on the mechanisms of GCS-mediated immunosuppression.

The atopic skin‐like microenvironment modulates the T‐cell‐polarising cytokine production of myeloid dendritic cells, as determined by laser scanning cytometry

“…Consistent with the results of our study, Lebre et al (20) found that CD1c+ DCs exhibit aberrant functions in AD patients because these cells could not induce a Th1 immune response, even in the presence of a strong Th1 stimulus. Due to the prevalent initiator but complex nature of mDCs in the skin's immune system, many therapeutic approaches target these cells via modifications of their function or the surrounding tissue microenvironment, that is, topical treatment of AD with calcineurin inhibitors and corticosteroids (21,22). Therefore, it is important to develop methods that are suitable for the investigation of the direct effects of newly developed therapies on DCs.…”

Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases

“…In our experiments, we also observed that unstimulated mDCs had a similar capacity to polarise Th1 cells in atopic and non-atopic individuals; however, this ability of atopic mDCs became impaired after stimulation. Consistent with the results of our study, Lebre et al (20) found that CD1c+ DCs exhibit aberrant functions in AD patients because these cells could not induce a Th1 immune response, even in the presence of a strong Th1 stimulus.Due to the prevalent initiator but complex nature of mDCs in the skin's immune system, many therapeutic approaches target these cells via modifications of their function or the surrounding tissue microenvironment, that is, topical treatment of AD with calcineurin inhibitors and corticosteroids (21,22). Therefore, it is important to develop methods that are suitable for the investigation of the direct effects of newly developed therapies on DCs.…”

“…Due to the prevalent initiator but complex nature of mDCs in the skin's immune system, many therapeutic approaches target these cells via modifications of their function or the surrounding tissue microenvironment, that is, topical treatment of AD with calcineurin inhibitors and corticosteroids (21,22). Therefore, it is important to develop methods that are suitable for the investigation of the direct effects of newly developed therapies on DCs.…”

Effects of Anthropogenic Events and Viral Persistence on Rodent Reservoirs of Hantavirus Infection: Understanding Host-Pathogen Interactions Facilitates Novel Approaches to Intervention Strategies

“…GCs are responsible for reducing the resistance of wild animals to viruses and increase their tolerance to harbouring the virus in a minimal range without causing any disease [15]. The possibility has been suggested that by activating organ-specific regulatory mechanisms GCs also influence the host-pathogen interaction [16,17].…”

“…When challenged by chronic anthropogenic stressors, immunologically suppressed rodents express elevated levels of GCs which mediate an organ-specific regulation that supports tolerance while removing resistance to hantavirus infection [15]. GCs block inflammatory pathways and induce apoptosis mediated by T reg lymphocytes [17,105,106,107]. GCs not only suppress differentiation of DC but also induce production of tolerogenic DC which express elevated IL-10 and TGF-β.…”