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

项目摘要/摘要 稳定驻留在外周组织中的淋巴细胞在抵御外来病原体方面发挥着关键作用， 抑制肿瘤发生，促进器官修复。其中许多细胞首先在周围组织中站稳脚跟 在出生后早期发育的“关键窗口”期间，并在一生中保持在特定的 微解剖位，为它们的生存和功能提供必要的因素。了解组织如何 居民淋巴细胞的建立和维护对我们尝试从功能上 操控这些细胞以达到治疗的效果。组织驻留淋巴细胞和/或其组织微环境中的异常 被认为会导致自身免疫和过敏性炎症。我们发现调节性T细胞(Tregs)在 新生儿皮肤在抑制组织中辅助性T细胞2型(Th2)的形成方面起着主要作用。 新生小鼠中Tregs的短暂丢失导致一种新的基质细胞亚群异常生长，该亚群 优先表达与2型免疫反应有关的基因(称为“2型基质细胞”或“2型干细胞”)。 同时，Th2细胞群在与2型干细胞相同的皮肤区域建立居留并持续到 成年，在完全修复Treg隔间很久之后。我们假设新生儿Treg功能障碍 在生命早期，成年后容易产生异常的Th2免疫反应，这是通过促进 皮肤中致病的Th2细胞生态位。先天性Tregs缺失的人Th2免疫反应失调 皮肤和发展严重特应性皮炎(AD)。因此，我们进一步假设，在生命早期，Treg功能障碍 有助于人类AD的发展，AD皮肤中Tregs的增加将优先抑制 这就是豁免权。该提案中概述的实验将全面定义皮肤中的Th2利基并确定 这一利基对特应性炎症的终生易感性的影响。我们首先要机械地测试一下 2型干细胞支持Th2细胞，并决定Th2细胞聚集和维持所需的分子因子。 皮肤。然后我们将测试新生儿生活中Th2小生境的建立是否易患特应性炎症 成年后AD相关的抗菌素免疫反应异常。最后，我们将决定我们的 研究结果适用于阿尔茨海默病患者。我们将阐明AD儿童患者的Tregs是否存在皮肤缺陷， 这些患者中是否存在2型SC-Th2细胞轴，以及Treg增强是否可以抑制Th2免疫 AD皮肤的反应。我们在皮肤中发现了一种新的基质细胞群，并拥有从基因上 操纵这些细胞，让我们能够测试一种新的假说，这种假说以免疫细胞壁龛的组织印记为中心 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, 我们将使用一种新的人体皮肤和新产生的蛋白质进行体外功能测试，这种蛋白质可以选择性地和 有效地激活了特雷格斯。因此，本提案中概述的实验代表了一种创新、全面和 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生态位。

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.