Mechanisms used by skin dendritic cells to induce regulatory T cells

描述(申请人提供)：必须严格控制皮肤免疫反应，以预防炎症和过敏性疾病，如特应性皮炎、牛皮癣、接触性皮炎和寻常型天疱疮。Foxp3+调节性T细胞(T Regs)发挥关键作用 在皮肤免疫调节中的作用。T细胞可以在胸腺中自然产生，也可以在抗原提呈细胞，特别是树突状细胞(DC)的作用下，从外周血中的CD4+初始T细胞诱导产生。DC系统是复杂的，由不同的亚群组成，如皮肤迁移性朗格汉斯细胞，皮肤迁移性经典真皮DC和CD103+真皮DC，以及组织驻留DC。到目前为止，这些亚群中的每一个在诱导T调节中的相对作用一直是不确定的。利用一种新的方法，即在体内使用针对表面受体的单抗将抗原定向到不同的DC亚群，我们发现了强有力的证据，表明并不是所有的DC都有诱导 调节性T细胞，但皮肤迁移性DC在这一功能上表现出色。这一观察导致了 我的假设是，这些皮肤迁移性DC的亚集是由一组转录因子内在地编程来诱导这种类型的反应。此外，当地的环境/饮食因素也被描述为在T regs的产生中发挥作用。例如，维生素A活性化合物维甲酸与转化生长因子-β一起工作，已知在肠道中诱导T调节蛋白具有积极影响。同样，有大量的体外证据表明维生素D作用于DC和/或T细胞以产生耐受性表型。这项拟议研究的贡献预计是：1)识别DC固有的信号通路，将皮肤迁移性DC的亚群编程为T regs的诱导；2)确定维生素对DC和/或T细胞的作用 在体内，用于T调节子的产生，以及3)诱导的抑制活性的评价 特应性皮炎小鼠模型中的Tregs。我们准备开展拟议的研究，因为我们拥有在体内研究DC功能的所有必要工具，以及对DC亚群的丰富经验。在我的导师们的指导下，我计划在K99奖项阶段实现分子生物学方法和小鼠基因工程方面的全面培训。这个项目具有特别的相关性，因为在大多数皮肤炎症性疾病中，Tregs的数量在定性和/或定量上都发生了变化，表明它们在疾病的病理生理学中所起的作用。对DC介导的T-reg诱导机制的详细理解将有助于理解导致皮肤病出现的事件。此外，这一知识可能有助于开发新的治疗靶点以提高T reg，这反过来将导致炎症性皮肤病及其并发症的改善治疗。

DESCRIPTION (provided by applicant): Cutaneous immune responses must be tightly controlled to prevent inflammatory and allergic diseases, i.e., atopic dermatitis, psoriais, contact dermatitis, and pemphigus vulgaris. Foxp3+ regulatory T cells (T regs) play a critical role in skin immunoregulation. T regs can be naturally generated in the thymus, or can be induced de novo from CD4+ naive T cells in the periphery by antigen presenting cells, especially dendritic cell (DCs). The DC system is intricate and is comprised of distinct subsets such as, skin migratory Langerhans cells, skin migratory classical dermal DCs and CD103+ dermal DCs, and tissue-resident DCs. The relative role of each of these subsets in inducing T regs has been until now indeterminate. Using a novel approach that consists of directing antigens to different subsets of DCs in vivo using monoclonal antibodies against surfac receptors, we have found strong evidence that not all DCs have the ability to induce regulatory T cells, but instead skin migratory DC excel in this function. This observation leads to my hypothesis that these subsets of skin migratory DC are intrinsically programmed by a set of transcriptional factors to induce this type of response. Additionally, local environmental/dietary factors are also described to play a role in the generation of T regs. For instance, the vitamin A active compound retinoic acid, working in conjunction with TGF-¿, is known to have a positive impact in the induction of T regs in the intestinal track. Similarly, ther is ample evidence in vitro suggesting that Vitamin D acts on DCs and/or T cells for generation of a tolerogenic phenotype. The contribution of the proposed research is expected to be: 1) the identification of DC-intrinsic signaling pathways that program subsets of skin migratory DC to the induction of T regs, 2) the determination of the role of Vitamins, acting on DCs and/or T cells in vivo, for the generation of T regs, and 3) the evaluation of the suppressive activity of induced Tregs in a mouse model of atopic dermatitis. We are prepared to undertake the proposed research since we have all the necessary tools for studying DC functions in vivo, as well as, ample experience with DC subsets. With my mentors, I have planned the aims to achieve a comprehensive training in molecular biology approaches and mouse genetic engineering during the K99 phase of the award. This project is of particular relevance because in most skin inflammatory diseases the number of T regs is altered, qualitatively and/or quantitatively, suggesting their role in the pathophysiology of the illness. A detailed comprehension of the mechanisms of DC-mediated T reg induction will help to understand the events that lead to the appearance of skin disease. Also, this knowledge is likely to be beneficial to the development new therapeutic targets to increase T reg, which in turn will lead to improved treatment of inflammatory skin diseases and their complications.