Mechanisms used by skin dendritic cells to induce regulatory T cells

描述（由申请人提供）：必须严格控制皮肤免疫应答，以预防炎症和过敏性疾病，即， 特应性皮炎、银屑病、接触性皮炎和寻常天疱疮。 Foxp 3+调节性T细胞（T细胞）在免疫调节中发挥关键作用。 皮肤免疫调节作用。T细胞可以在胸腺中天然产生，也可以由抗原呈递细胞，特别是树突状细胞（DC）从外周中的CD 4+初始T细胞从头诱导。 DC系统是复杂的，并且由不同的亚群组成，例如皮肤迁移性朗格汉斯细胞、皮肤迁移性经典真皮DC和CD 103+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细胞中的相对作用还不确定。使用一种新的方法，该方法包括使用针对表面受体的单克隆抗体在体内将抗原引导至不同的DC亚群，我们发现了强有力的证据，即并非所有的DC都具有诱导细胞凋亡的能力。 然而，在调节性T细胞中，皮肤迁移性DC在这一功能中表现出色。这一观察导致 我的假设是，这些皮肤迁移性DC的子集本质上是由一组转录因子编程的，以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细胞的产生中发挥作用。例如，维生素A活性化合物视黄酸，与TGF-β一起工作，已知对肠道中T细胞的诱导有积极影响。类似地，有充分的体外证据表明维生素D作用于DC和/或T细胞以产生致耐受性表型。 该研究的贡献在于：1）识别DC-内在信号通路，其编程皮肤迁移DC的亚群以诱导T细胞，2）确定Vitamin作用于DC和/或T细胞的作用 在体内，用于产生T细胞，和3）评估诱导的T细胞的抑制活性， 特应性皮炎小鼠模型中的TdR。我们准备进行拟议的研究，因为我们有所有必要的工具，在体内研究DC功能，以及丰富的经验与DC子集。与我的导师，我计划的目标是实现在K99阶段的奖励分子生物学方法和小鼠基因工程的全面培训。该项目是特别相关的，因为在大多数皮肤炎性疾病中，T细胞的数量在定性和/或定量上发生了改变，表明它们在疾病的病理生理学中的作用。 详细了解DC介导的T reg诱导的机制将有助于理解导致皮肤病出现的事件。 此外，这一知识可能有利于开发新的治疗靶点以增加T reg，这反过来将导致炎症性皮肤病及其并发症的治疗得到改善。 公共卫生相关性：树突状细胞（Dendritic cells，DC）是免疫系统中至关重要的细胞，其具有增加调节性T细胞（regulatory T cells，T细胞）数量的能力。T细胞是具有阻止有害的皮肤炎症反应的能力的特化免疫细胞，例如特应性皮炎、牛皮癣、接触性皮炎和寻常天疱疮。在这个提议中，我们将了解控制皮肤DC介导的大量T细胞生成的机制，最终目标是为了治疗目的在体内操纵这些反应。

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. PUBLIC HEALTH RELEVANCE: Dendritic cells (DCs) are critically important cells of the immune system, which have the capacity to increase the numbers of regulatory T cells (T regs). T regs are specialized immune cells with the ability to stop detrimental skin inflammatory responses, such as atopic dermatitis, psoriasis, contact dermatitis, and pemphigus vulgaris. In this proposal, we will understand the mechanisms that govern skin DC-mediated generation of high numbers of T regs, with the eventual goal of manipulating these responses in vivo for therapeutic purposes.