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.

先天性T细胞学习在皮肤中找到它们的活化配体， 使用胆固醇副产物的胸腺教育 总结 异位性皮炎（AD）等异常皮肤炎性疾病是一种猖獗的疾病 在发达国家的儿童中，多达四分之一的儿童患有这种疾病。AD 已知是一种过敏性T细胞疾病，当皮肤屏障变得 退化了在鉴定组织屏障相关基因方面取得了进展 防御工事这些基因突变的人易患过敏性疾病 淋巴细胞介导的疾病，但大多数具有遗传易感性的个体仍然 并不发展疾病，这表明存在免疫机制， 有害的炎症反应。我们发现皮肤先天性T细胞的缺失 程序化分泌IL-17和IL-22的淋巴细胞导致小鼠自发性AD 人类AD的所有主要特征，将这些称为Tγδ17的细胞作为顶点， 皮肤稳态的调节器。小鼠真皮Tγδ17细胞仅在新生期发育 它们是在胸腺中制造的，以便它们在播种时能够快速反应。 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细胞学会定位于 胸腺中的相关皮肤部位。这种胸腺教育通过限制成熟而发生 Tγδ17胸腺细胞可以通过G蛋白感知胆固醇副产物氧固醇 偶联受体（GPCR）GPR 183（Ebi 2）和/或CCR 6趋化因子受体配体 CCL20。在非炎症环境中，例如在健康新生儿中，GPR 183 + CCR 6 + Tγδ17细胞离开胸腺，并使用CCR 6进入皮肤，然后精细定位在胸腺中。 使用假定的氧固醇梯度对真皮进行染色。这是一个高风险高回报的项目， 旨在确定氧固醇对先天性T细胞定位的至关重要性， 身体概念基础是独特的，因为全球化学品保护没有先例- 淋巴细胞在起源组织中的依赖性成熟， 成熟的淋巴细胞预测组织中相同线索的能力， 功能这种缺乏先例的做法使得项目存在风险，但如果被证明是准确的， 从根本上改变了我们对粘膜先天性T细胞感受 环境的改变和扩大胆固醇的功能域及其 副产品在建立和维持健康的免疫系统，特别是 新生儿