Arylhydrocarbon receptor (AhR) and UVR-induced immunosuppression

芳基烃受体 (AhR) 和 UVR 诱导的免疫抑制

• 批准号: 201682912
• 负责人: Professor Dr. Thomas Schwarz
• 金额: --
• 依托单位: Klinik für Dermatologie, Venerologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/201682912?language=en
• 关键词: Arylhydrocarbon; receptor; AhR; UVR; induced

Ultraviolet radiation (UVR) suppresses the immune system via induction of regulatory T cells (Treg) which because of their antigen-specificity may harbor therapeutic potential. To avoid the obligatory DNA damage which is associated with any UVR exposure, alternative strategies to induce Treg are required. In the initial proposal we demonstrated that activation of the arylhydrocarbon receptor (AhR), a ligand-activated transcription factor involved in the detoxification of aromatic hydrocarbons, by UVR seems to be an essential event in UVR-induced immunosuppression and the induction of Treg. In addition, we observed that in turn activation of the AhR by the specific agonistic ligand 4-n-nonylphenol induces T cells with suppressive features. In the current proposal it shall be studied whether Treg can be induced by other AhR agonists, whether and in how far AhR-induced Treg differ from UVR-induced Treg and whether they are suitable for therapeutic intervention. Furthermore, the cellular and molecular mechanisms underlying the induction of Treg by AhR activation shall be elucidated, with special focus on antigen-presenting cells and T cells. In addition, the molecular role of the AhR during UVR-induced immunosuppression shall be addressed; preliminary data imply that modulation of DNA repair by AhR activation is involved. The majority of studies will be performed in the model of allergic contact hypersensitivity in mice. Specific questions will be addressed by utilizing respective transgenic mouse models (DEREG, Langerin-DTR, Xpa-knock-out, AhR-Langerin-knock-out, AhR-CD11c-knock out, AhR-K5-knock-out).

紫外线辐射（UVR）通过诱导调节性T细胞（Treg）抑制免疫系统，由于其抗原特异性可能具有治疗潜力。为了避免与任何UVR暴露相关的强制性DNA损伤，需要其他策略来诱导Treg。在最初的提案中，我们证明了UVR激活芳烃受体（AhR），一种参与芳烃解毒的配体激活转录因子，似乎是UVR诱导免疫抑制和诱导Treg的必要事件。此外，我们观察到，特异性激动性配体4-n-壬基酚反过来激活AhR诱导T细胞具有抑制特征。在目前的提案中，需要研究其他AhR激动剂是否可以诱导Treg， AhR诱导的Treg与uvr诱导的Treg是否存在差异，差异有多大，是否适合用于治疗干预。此外，AhR活化诱导Treg的细胞和分子机制将被阐明，特别关注抗原提呈细胞和T细胞。此外，AhR在uvr诱导的免疫抑制中的分子作用也将得到解决；初步数据表明，AhR激活对DNA修复的调节参与其中。大多数研究将在小鼠过敏性接触超敏反应模型中进行。具体问题将通过利用各自的转基因小鼠模型（DEREG, Langerin-DTR， xpa -敲除，ahr - langerin -敲除，ahr - cd11c -敲除，ahr - k5敲除）来解决。