Mechanisms used by skin dendritic cells to induce regulatory T cells

皮肤树突状细胞诱导调节性 T 细胞的机制

• 批准号: 9115905
• 负责人: Juliana Idoyaga
• 金额: $ 24.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115905
• 关键词: Allergic Disease; Antigen Targeting; Antigen-Presenting Cells; Antigens; Appearance; Atopic Dermatitis; Award; Cell physiology; Cells; Comprehension; Contact Dermatitis; Cutaneous; Data; Data Reporting; Dendritic Cells; Dermal; Development; Dietary Factors; Disease; Dominant-Negative Mutation; Environment; Environmental Risk Factor; Evaluation; Event; Faculty; Foundations; Functional disorder; Generations; Genetic Transcription; Goals; Immune; Immune response; Immune system; Immunology; In Situ; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intestines; Knockout Mice; Knowledge; Langerhans cell; Lead; Lymphoid Tissue; Mediating; Mentors; Microarray Analysis; Modeling; Molecular; Monoclonal Antibodies; Mus; Pathology; Pemphigus Vulgaris; Phase; Phenotype; Play; Population; Positioning Attribute; Psoriasis; Regulatory T-Lymphocyte; Reporting; Research; Retinoic Acid Receptor; Role; Signal Pathway; Signal Transduction; Skin; Staging; Surface; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thymus Gland; Tissues; Training; Tretinoin; Universities; Vitamin A; Vitamin D; Vitamins; Work; career; differential expression; experience; immunoregulation; improved; in vivo; langerin; lymph nodes; microbiota; mouse model; new therapeutic target; novel strategies; prevent; programs; receptor; research study; response; skills; skin disorder; tool; transcription factor

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.

必须严格控制皮肤免疫反应，以预防炎症性和过敏性疾病，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(Tregs)在皮肤免疫调节中起重要作用。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+幼稚T细胞中诱导产生。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不清楚。使用一种新的方法，即在体内使用抗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，并不是所有的DC都具有诱导调节性T细胞的能力，相反，皮肤迁移性DC在这一功能上表现出色。这一观察结果导致了我的假设，即这些皮肤迁移性树突状细胞亚群内在地由一组转录因子编程来诱导这种类型的反应。此外，当地的环境/饮食因素被描述为在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-B共同作用，已知在肠道诱导T-regs方面有积极影响。同样，体外有大量证据表明维生素D作用于DC和/或T细胞以产生耐受性表型。此外，微生物区系最近被证明在调节皮肤免疫反应方面发挥着重要作用。预计这项研究的贡献在于：1)识别DC固有的信号通路，将皮肤迁移性DC亚群编程为T regs的诱导；2)确定维生素和微生物区系在作用于体内DC和/或T细胞产生T regs的作用；以及3)在特应性皮炎小鼠模型中评估诱导的T regs的抑制活性。我准备从事这项拟议的研究，因为我拥有在体内研究DC功能的所有必要工具，以及丰富的DC亚群经验。在该奖项的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及其对初级教员的承诺是我过渡到独立教师的理想选择。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。