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.

先天的T细胞学会在皮肤中找到其激活的配体 使用胆固醇副产品的胸腺教育 概括 异常皮肤炎症性疾病（如特应性皮炎（AD））是一种猖ramp的疾病 在发达国家的儿童中，其中多达四分之一遭受了困扰。广告 已知是一种过敏性T细胞的疾病，当皮肤屏障变为 退化。在识别涉及组织屏障的基因方面取得了进展 筑城。这些基因突变的人易于过敏 由淋巴细胞介导的疾病，但大多数具有遗传敏感性的人仍然 不要发展疾病，表明存在免疫机制可以跳舞 有害炎症反应。我们发现缺乏真皮先天 编程以分泌IL-17和IL-22的淋巴细胞在小鼠中产生赞助广告 在人类AD的所有主要标志上，将这些称为Tγδ17的细胞作为顶点 鼠皮肤Tγδ17细胞仅在新生儿期间发展 阶段，它们是在胸腺中制成的，以便在播种时可以快速反应 皮肤。但是，这些皮肤调节细胞如何定位于真皮。在这个 项目我们将测试开发Tγδ17细胞学习本地化的假设 胸腺中相关的皮肤部位。这种胸腺教育是通过限制成熟而发生的 Tγδ17的胸腺细胞可以通过G蛋白感知胆固醇副产品氧 耦合受体（GPCR）GPR183（EBI2）和/或CCR6趋化因子受体配体 CCL20。在非炎症环境中，例如在健康的新生儿中，GPR183+CCR6+ Tγδ17细胞退出胸腺并使用CCR6进入皮肤，然后在 真皮使用推定的氧醇梯度。这是一个高风险和高奖励项目， 旨在确定氧蛋白酶对先天T细胞定位的至关重要性 身体。概念基础是独特的，因为GPCR-没有先例 依赖性淋巴细胞在原产组织中紧密相连 具有成熟淋巴细胞在组织中预期相同提示的能力 功能。缺乏先例会使项目冒险，但是如果被证明是准确的， 从根本上改变了我们对粘膜先天T细胞传感器的理解 环境改变并扩大胆固醇及其功能领域 在建造和维护健康的免疫系统方面的副产品，尤其是在 新生儿。