Mechanisms used by skin dendritic cells to induce regulatory T cells

必须严格控制皮肤免疫应答以预防炎性和过敏性疾病，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）在皮肤免疫调节中起关键作用。T细胞可以在胸腺中天然产生，或者可以通过抗原呈递细胞，特别是树突状细胞（DC）从外周中的CD 4+幼稚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、CD 103+真皮DC和组织驻留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清楚。使用一种新的方法，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表明，并非所有的DC都具有诱导调节性T细胞的能力，而是皮肤迁移性DC在这一功能中表现出色。这一观察结果导致我的假设，这些皮肤迁移性DC的子集本质上是由一组转录因子编程，以诱导这种类型的反应。此外，当地的环境/饮食因素已被描述为在T β的产生中发挥作用。例如，已知维生素A活性化合物视黄酸与TGF-β协同作用，对肠道中的TGF-β诱导具有积极影响。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。此外，微生物群最近已被证明在调节皮肤免疫应答中起重要作用。预计拟议研究的贡献是：1）识别DC内在信号通路，其编程皮肤迁移DC的子集以诱导T细胞; 2）确定维生素和微生物群在体内作用于DC和/或T细胞以产生T细胞的作用;和3）评估诱导的T细胞在特应性皮炎小鼠模型中的抑制活性。我准备进行拟议的研究，因为我有所有必要的工具，在体内研究DC功能，以及丰富的经验与DC子集。在K99阶段获得的数据和技能为成功的ROO阶段奠定了坚实的基础。斯坦福大学优良的科学环境和对初级教师的承诺是我向独立过渡的理想选择。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，这反过来又会改善炎症性皮肤病及其并发症的治疗。

Cutaneous immune responses must be tightly controlled to prevent inflammatory and allergic diseases, i.e., atopic dermatitis, psoriasis, 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 nova from CD4+ naïve T cells in the periphery by antigen presenting cells, especially dendritic cells (DCs). The DC system is intricate and is comprised of distinct subsets such as skin migratory Langerhans cells, skin migratory classical dermal DCs, CD 103+ dermal DCs, and tissue-resident DCs. The relative role of each of these subsets in inducing T regs has been until now unclear. Using a novel approach that consists of directing antigens to different subsets of DCs in vivo using monoclonal antibodies against surface receptors, we have found strong evidence that not all DCs have the ability to induce regulatory T cells, but instead skin migratory DCs excel in this function. This observation leads to my hypothesis that these subsets of skin migratory DCs are intrinsically programmed by a set of transcriptional factors to induce this type of response. Additionally, local environmental/dietary factors have been described as playing a role in the generation of T regs. For instance, the vitamin A active compound retinoic acid, working in conjunction with TGF- ß is known to have a positive impact in the induction of T regs in the intestinal tract. Similarly, there is ample evidence in vitro suggesting that vitamin D acts on DCs and/or T cells for the generation of a tolerogenic phenotype. Further, microbiota have recently been shown to play an important role in modulating skin immune responses. 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 and microbiota, acting on DCs and/or T cells in vivo, to generate T regs; and 3) the evaluation of the suppressive activity of induced T regs in a mouse model of atopic dermatitis. I am prepared to undertake the proposed research since I have all the necessary tools for studying DC functions in vivo, as well as ample experience with DC subsets. The data and skills acquired during the K99 phase of this award have laid a strong foundation for a successful ROO phase. The excellent scientific environment at Stanford University and its commitment to junior faculty are ideal for my transition to independence. 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 diseases. Also, this knowledge is likely to be beneficial for the development of new therapeutic targets to increase T reg, which in turn will lead to improved treatment of inflammatory skin diseases and their complications.