Innate T cells learn to find their activating ligands in the skin during their thymic education using cholesterol byproducts

先天 T 细胞在胸腺教育过程中利用胆固醇副产物学会寻找皮肤中的激活配体

• 批准号: 9763936
• 负责人: Joonsoo Kang
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-21 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763936
• 关键词: 25-hydroxycholesterol; Acute; Allergic Disease; Anatomy; Antigen-Presenting Cells; Atopic Dermatitis; CCL20 gene; CCR6 gene; Cell Maturation; Cells; Child; Cholesterol; Chronic; Confocal Microscopy; Coupled; Cues; Defect; Dermal; Dermis; Developed Countries; Developing Countries; Development; Disease; Education; Ensure; Enzymes; Epithelial; Epithelial Cells; Future; G-Protein-Coupled Receptors; Generations; Genes; Genetic; Genetic Predisposition to Disease; Homeostasis; Human; Image; Immune; Immune response; Immune system; Immunity; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Institutes; Interleukin-17; Learning; Ligands; Link; Lung; Lymphocyte; Lymphoid Cell; Maps; Mature Lymphocyte; Mediating; Mixed Function Oxygenases; Mucous Membrane; Mus; Mutation; Neonatal; Newborn Infant; Phenocopy; Positioning Attribute; Process; Production; Property; Psoriasis; Relapse; Reporter; Rest; Seeds; Sentinel; Site; Skin; Source; Susceptibility Gene; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Training; autoinflammatory; cell type; chemokine receptor; cholesterol biosynthesis; commensal bacteria; cytokine; design; dysbiosis; fitness; fortification; high reward; high risk; imprint; insight; interleukin-22; interleukin-23; neonate; pathogen; prevent; response; skin barrier; skin disorder; thymocyte; two-photon

Innate T cells learn to find their activating ligands in the skin during their thymic education using cholesterol byproducts Summary Aberrant skin inflammatory disorder such as atopic dermatitis (AD) is a rampant disease among children of developed countries, with as many as a quarter of them afflicted. AD is known to be a disease of allergic T cells that manifest when the skin barrier becomes degraded. There has been progress in identifying genes involved in tissue barrier fortification. People with mutations in these genes are predisposed towards allergic diseases mediated by lymphocytes, but most individuals with genetic susceptibility still do not develop the diseases, suggesting that there exist immune mechanisms to dampen harmful inflammatory responses. We discovered that an absence of dermal innate T lymphocytes programmed to secrete IL-17 and IL-22 results in spontaneous AD in mice with all major hallmarks of human AD, placing these cells called Tγδ17 as the apex regulator of skin homeostasis. Murine dermal Tγδ17 cells develop only during neonatal stages and they are made in the thymus so that they can respond fast when they seed the skin. However, how these skin regulatory cells localize to the dermis is not known. In this project we will test the hypothesis that developing Tγδ17 cells learn to localize in the relevant skin sites in the thymus. This thymic education occurs by restricting maturation of Tγδ17 thymocytes that can sense cholesterol byproducts oxysterols via the G protein coupled receptor (GPCR) GPR183 (Ebi2) and/or the CCR6 chemokine receptor ligand CCL20. In non-inflammatory settings, such as in healthy neonates, GPR183+CCR6+ Tγδ17 cells exit the thymus and enter the skin using CCR6 and then fine-localize in the dermis using the putative oxysterol gradient. This is a high risk and high reward project, designed to establish the critical importance of oxysterols for innate T cell positioning in the body. The conceptual basis is unique as there are no precedents for the GPCR- dependent maturation of lymphocytes in the tissues of origin that are intimately linked to the ability of mature lymphocytes to anticipate the same cues in the tissues of function. This lack of precedent makes the project risky, but if proven to be accurate will fundamentally alter our understanding of mucosal innate T cell sensing of environmental alterations and expand the functional domains of cholesterol and its byproducts in building and maintaining a healthy immune system, especially in newborns.

先天T细胞学习在皮肤中找到它们的激活配体 利用胆固醇副产品进行胸腺教育 摘要 特应性皮炎(AD)等异常皮肤炎症性疾病是一种常见的疾病 在发达国家的儿童中，多达四分之一的儿童患有这种疾病。广告 已知是一种过敏性T细胞疾病，当皮肤屏障变成 降级了。在识别与组织屏障有关的基因方面取得了进展 设防。携带这些基因突变的人容易过敏 由淋巴细胞介导的疾病，但大多数有遗传易感性的人仍然 不发展的疾病，这表明存在免疫机制，以抑制 有害的炎症反应。我们发现，缺乏皮肤上的先天T细胞 分泌IL-17和IL-22的淋巴细胞导致小鼠自发性阿尔茨海默病 利用人类AD的所有主要特征，将这些名为Tγδ17的细胞放置在顶端 皮肤动态平衡调节剂。小鼠皮肤Tγδ17细胞仅在新生期发育 阶段，它们是在胸腺中制造的，所以当它们播种到 皮肤。然而，这些皮肤调节细胞如何定位于真皮尚不清楚。在这 我们将测试这一假设，即发育中的Tγδ17细胞学习定位于 胸腺中的相关皮肤部位。这种胸腺教育是通过限制成熟来进行的。 Tγδ17胸腺细胞中可通过G蛋白感知胆固醇副产物氧合甾醇 偶联受体GPR183(EBI2)和/或CCR6趋化因子受体配体 CCL20。在非炎症性环境中，如健康新生儿，GPR183+CCR6+ Tγδ17细胞通过CCR6离开胸腺进入皮肤，然后在胸腺中进行精细定位 真皮使用假定的氧固醇梯度。这是一个高风险、高回报的项目， 旨在确定氧化甾醇对先天T细胞定位的关键重要性 身体。概念基础是独一无二的，因为没有GPCR的先例- 起源组织中紧密相连的淋巴细胞的依赖成熟 成熟淋巴细胞在组织中预测相同线索的能力 功能。这种缺乏先例的做法使该项目具有风险，但如果被证明是准确的，将会 从根本上改变我们对粘膜固有T细胞感知的理解 环境变化与胆固醇及其功能域的拓展 建立和维护健康的免疫系统的副产品，特别是在 新生儿。