Mechanisms used by skin dendritic cells to induce regulatory T cells

皮肤免疫反应必须严格控制，以防止炎症和过敏性疾病，即特应性皮炎、牛皮癣、接触性皮炎和寻常性天疱疮。Foxp3+调节性T细胞（T regs）在皮肤免疫调节中起关键作用。T regs可以在胸腺中自然产生，也可以通过抗原提呈细胞，特别是树突状细胞（DCs），从周围的CD4+ naïve T细胞中诱导生成。DC系统错综复杂，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、cd103 +真皮DC和组织常驻DC。到目前为止，这些亚群在诱导T regs中的相对作用还不清楚。使用一种新颖的方法，包括使用针对表面受体的单克隆抗体在体内将抗原引导到不同的dc亚群，我们发现了强有力的证据，表明并非所有dc都具有诱导调节性T细胞的能力，而是皮肤迁移dc具有这种功能。这一观察结果导致了我的假设，即这些皮肤迁移dc的亚群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，当地环境/饮食因素也被认为在T regs的产生中起作用。例如，已知维生素A活性化合物维甲酸与TGF- ß联合作用，对诱导肠道T regs有积极影响。同样，有充分的体外证据表明，维生素D对dc和/或T细胞起作用，产生耐受性表型。此外，微生物群最近被证明在调节皮肤免疫反应中发挥重要作用。预计该研究的贡献在于：1)确定DC-内在信号通路，该通路可将皮肤迁移DC亚群编程为T regs的诱导；2)测定体内作用于dc和/或T细胞的维生素和微生物群产生T regs的作用；3)小鼠特应性皮炎模型中诱导T regs抑制活性的评价。我已经准备好进行这项研究，因为我拥有研究体内DC功能的所有必要工具，以及丰富的DC子集经验。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。斯坦福大学优秀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。这个项目是特别相关的，因为在大多数皮肤炎症性疾病中，T细胞的数量是改变的，定性和/或定量，表明它们在疾病的病理生理中的作用。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疾病出现的事件。此外，这一知识可能有助于开发新的治疗靶点来增加T reg，这反过来将导致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.