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 细胞在其生命周期中学会寻找皮肤中的激活配体。 使用胆固醇副产品进行胸腺教育 概括 异常皮肤炎症性疾病，如特应性皮炎 (AD) 是一种猖獗的疾病 发达国家的儿童中，有多达四分之一患有AD。 众所周知，这是一种过敏性 T 细胞疾病，当皮肤屏障变得 在鉴定参与组织屏障的基因方面已取得进展。 这些基因突变的人容易过敏。 由淋巴细胞介导的疾病，但大多数具有遗传易感性的个体仍然 不发展疾病，表明存在抑制免疫机制 我们发现真皮先天 T 的缺失。 淋巴细胞编程分泌 IL-17 和 IL-22 导致小鼠自发性 AD 具有人类 AD 的所有主要特征，将这些称为 Tγδ17 的细胞作为顶点 皮肤稳态的调节因子。小鼠真皮 Tγδ17 细胞仅在新生儿期发育。 它们是在胸腺中形成的，因此当它们播种时可以快速做出反应 然而，这些皮肤调节细胞如何定位于真皮尚不清楚。 项目中，我们将测试以下假设：正在发育的 Tγδ17 细胞学会在 这种胸腺教育是通过限制成熟来实现的。 Tγδ17 胸腺细胞可以通过 G 蛋白感知胆固醇副产物氧甾醇 偶联受体 (GPCR) GPR183 (Ebi2) 和/或 CCR6 趋化因子受体配体 CCL20 在非炎症环境中，例如健康新生儿，GPR183+CCR6+。 Tγδ17 细胞利用 CCR6 离开胸腺并进入皮肤，然后精细定位于 使用假定的氧甾醇梯度进行真皮这是一个高风险和高回报的项目， 旨在确定氧甾醇对于先天 T 细胞定位的至关重要性 该机构的概念基础是独特的，因为 GPCR 没有先例。 密切相关的起源组织中淋巴细胞的依赖性成熟 成熟淋巴细胞预测组织中相同信号的能力 缺乏先例使得该项目存在风险，但如果被证明是准确的，将会存在风险。 从根本上改变我们对粘膜先天T细胞感知的理解 环境改变并扩大胆固醇及其功能域 建立和维持健康免疫系统的副产品，尤其是 新生儿。