Glucocorticosteroids modify Langerhans cells to produce TGF-β and expand regulatory T cells.
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.
Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria. georg.stary@meduniwien.ac.at
Georg
G
Stary
Irene
I
Klein
Wolfgang
W
Bauer
Frieder
F
Koszik
Bärbel
B
Reininger
Sabine
S
Kohlhofer
Kristina
K
Gruber
Hans
H
Skvara
Thomas
T
Jung
Georg
G
Stingl
D000284:Administration, Oral; D000328:Adult; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000008:administration & dosage; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009532:Nickel / Q000008:administration & dosage / Q000276:immunology; D010328:Patch Tests / Q000379:methods; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology*; D015203:Reproducibility of Results; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D055815:Young Adult
D000485:Allergens; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta; D009532:Nickel; D011241:Prednisone