Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.
J Immunol. 2011 Jan 1;186(1):103-12. doi: 10.4049/jimmunol.1002485. Epub 2010 Dec 6.
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.
尽管糖皮质激素（GCS）在移植和（自身）炎症性疾病中已使用了数十年，但它们具有免疫抑制特性的确切机制仍未完全阐明。本研究的目的是研究口服 GCS 对皮肤免疫反应的影响。我们通过免疫荧光染色和定量 RT-PCR 分析了我们曾使用口服 GCS 作为阳性对照来确定候选抗炎化合物对镍过敏患者经皮斑贴试验影响的临床研究中的残留皮肤活检材料。正如预期的那样，口服 GCS 治疗可减轻临床症状和浸润的白细胞。值得注意的是，我们观察到真皮 FOXP3(+)CD25(+)T 细胞和表皮朗格汉斯细胞（LCs）的数量增加，这些细胞与 GCS 治疗的镍过敏患者病变中 TGF-β 的 mRNA 表达上调有关。为了进一步研究这一现象，我们将纯化的 LCs 暴露于 GCS 中。与未暴露于 GCS 的 LCs 相比，它们表现出 1）更不成熟的表型，2）更高的细胞内 TGF-β含量，和 3）NF-κB 受体激活剂表达增加，这些条件据报道有利于调节性 T 细胞（Tregs）的扩增。实际上，当用 GCS 预处理的 LCs 孵育 CD3(+)细胞时，我们观察到功能性抑制性 FOXP3(+)T 细胞的增强。仅通过 TGF-β 阻断即可抑制 Tregs 的扩增，并且通过 TGF-β 和抗 IL-10 Abs 的组合可以中和其抑制活性。我们的数据表明，系统应用的 GCS 赋予 LCs 促进 Treg 的特性，从而为 GCS 介导的免疫抑制机制提供了新的见解。
