Elucidating the Role of Regulatory T cells in Establishing and Maintaining a Th2 Niche in Skin

阐明调节性 T 细胞在皮肤中建立和维持 Th2 生态位的作用

• 批准号: 10214537
• 负责人: Michael David Rosenblum
• 金额: $ 68.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214537
• 关键词: Ablation; Adult; Affect; Affinity; Allergic inflammation; Anatomy; Applications Grants; Atopic Dermatitis; Attenuated; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cells; Cellular biology; Chronic; Coculture Techniques; Cre driver; Cutaneous; Development; Disease; Disease model; Fibronectins; Functional disorder; Genes; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Host Defense; Human; Immune; Immune Tolerance; Immune response; Immunity; Inflammation; Inflammatory; Integrin alpha4; Interleukin 2 Receptor; Lead; Life; Ligands; Link; Lymphocyte; Lymphocyte Subset; Maintenance; Microbe; Molecular; Mus; Neonatal; Organ; Pathogenicity; Pathway interactions; Patients; Peripheral; Phenotype; Play; Population; Predisposition; Process; Proteins; Regulatory T-Lymphocyte; Role; Skin; Staphylococcus aureus; Stromal Cells; T cell response; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Time; Tissues; Translating; antimicrobial; antimicrobial peptide; autoimmune inflammation; commensal microbes; cytokine; dysbiosis; experimental study; genetic manipulation; human disease; immune activation; imprint; in vivo; in vivo evaluation; innovation; innovative technologies; insight; interdisciplinary approach; microbial; mouse model; neonatal mice; novel; novel therapeutic intervention; pathogen; pediatric patients; postnatal; postnatal development; prevent; receptor; repaired; residence; response; restoration; selective expression; single-cell RNA sequencing; skin disorder; skin organogenesis; tissue repair; tool; tumor; tumorigenesis

Project Summary/Abstract Lymphocytes that stably reside in peripheral tissues play a critical role in defending against foreign pathogens, suppressing tumorigenesis and facilitating organ repair. Many of these cells first establish themselves in peripheral tissues during “critical windows” of early postnatal development and are maintained throughout life within specific microanatomic niches, which provide the necessary factors for their survival and function. Understanding how tissue resident lymphocytes are established and maintained is of fundamental importance in our attempts to functionally manipulate these cells for therapeutic benefit. Abnormalities in tissue-resident lymphocytes and/or their tissue niches are thought to contribute to autoimmune and allergic inflammation. We have discovered that regulatory T cells (Tregs) in neonatal skin play a major role in suppressing the formation of a niche for T helper type 2 (Th2) cells in this tissue. Transient loss of Tregs in neonatal mice results in the aberrant outgrowth of a novel subset of stromal cells that preferentially express genes involved in type 2 immune responses (termed 'type 2 stromal cells' or `type 2 SCs'). Concurrently, a population of Th2 cells establishes residence in the same region of skin as type 2 SCs and persists into adulthood, long after complete restoration of the Treg compartment. We hypothesize that neonatal Treg dysfunction early in life predisposes to aberrant Th2 immune responses in adulthood by facilitating the establishment of a pathogenic Th2 cell niche in skin. Humans with congenital loss of Tregs have dysregulated Th2 immune responses in skin and develop severe atopic dermatitis (AD). Thus, we further postulate that Treg dysfunction early in life contributes to the development of human AD and that augmenting Tregs in AD skin will preferentially suppress Th2 immunity. Experiments outlined in this proposal will comprehensively define the Th2 niche in skin and determine the consequences of this niche for lifelong susceptibility to atopic inflammation. We will first mechanistically test whether type 2 SCs support Th2 cells and determine the molecular factors necessary for Th2 cell accumulation and maintenance in the skin. We will then test whether the establishment of the Th2 niche in neonatal life predisposes to atopic inflammation and aberrant AD-associated antimicrobial immune responses in adulthood. Finally, we will determine whether our findings translate to patients with AD. We will elucidate whether Tregs are defective in skin of pediatric patients with AD, whether a type 2 SC-Th2 cell axis exists in these patients, and whether Treg augmentation can suppress Th2 immune responses in AD skin. We have discovered a new stromal cell population in skin and have the tools to genetically manipulate these cells, allowing us to test a novel hypothesis centered around 'tissue imprinting' of immune cell niches early in life. We will utilize highly innovative technology to quantify T cell responses to cutaneous microbes. In addition, we will employ a novel ex vivo functional assay with human skin and a newly generated protein that selectively and potently activates Tregs. Thus, the experiments outlined in this proposal represent an innovative, comprehensive, and multidisciplinary approach to elucidate the cellular and molecular mechanisms that underpin cutaneous type 2 immune cell niches in both mouse models and in human disease.

项目总结/摘要 稳定驻留在外周组织中的淋巴细胞在防御外来病原体方面起着关键作用， 抑制肿瘤发生和促进器官修复。这些细胞中的许多首先在外周组织中建立自己 在出生后早期发育的“关键窗口”期间， 微解剖生态位，为它们的生存和功能提供必要的因素。了解组织如何 常驻淋巴细胞的建立和维持对于我们试图从功能上 操纵这些细胞以获得治疗益处。组织驻留淋巴细胞和/或其组织小生境中的脱落是 被认为是导致自身免疫性和过敏性炎症的原因。我们已经发现，调节性T细胞（T细胞）， 新生儿皮肤在抑制该组织中辅助性T细胞2型（Th 2）的小生境形成中起主要作用。 新生小鼠中TGF 1 α的短暂缺失导致一种新的基质细胞亚群的异常生长， 优先表达参与2型免疫反应的基因（称为“2型基质细胞”或“2型SC”）。 同时，Th 2细胞群在与2型SC相同的皮肤区域中建立驻留，并持续到24小时。 成年期，Treg区室完全恢复后很久。我们假设新生儿Treg功能障碍 在生命早期，通过促进Th 2免疫应答的建立， 皮肤中的致病性Th 2细胞龛。先天性T细胞减少的人Th 2免疫应答失调， 皮肤和发展严重的特应性皮炎（AD）。因此，我们进一步假设，Treg功能障碍在生命早期 有助于人类AD的发展，并且增加AD皮肤中的TdR将优先抑制 Th 2免疫。本提案中概述的实验将全面定义皮肤中的Th 2小生境，并确定 这一生态位对特应性炎症终身易感性的后果。我们将首先从机械上测试 2型SC支持Th 2细胞，并决定Th 2细胞积累和维持所需的分子因子。 皮肤然后，我们将测试新生儿生命中Th 2小生境的建立是否易患特应性炎症 以及成年期AD相关的异常抗菌免疫反应。最后，我们将确定我们的 结果转化为AD患者。我们将阐明是否有缺陷的皮肤，儿童患者的皮肤AD， 这些患者中是否存在2型SC-Th 2细胞轴，以及Treg增强是否可以抑制Th 2免疫反应， AD皮肤的反应我们在皮肤中发现了一种新的基质细胞群，并有了从基因上 操纵这些细胞，使我们能够测试一个新的假设围绕'组织印记'的免疫细胞龛 在生命的早期。我们将利用高度创新的技术来量化T细胞对皮肤微生物的反应。此外，本发明还提供了一种方法， 我们将采用一种新的离体功能测定法，使用人皮肤和新产生的蛋白质， 能有效激活甲状腺激素因此，本提案中概述的实验代表了一种创新的，全面的， 多学科方法阐明支持皮肤2型免疫的细胞和分子机制 在小鼠模型和人类疾病中的细胞小生境。