Mucosal Associated Invariant T cells in the Obese-asthma endotype

摘要 哮喘是一种炎症性肺部疾病，影响着全球3亿人。虽然轻度哮喘是 在Th2相关、嗜酸性粒细胞主导的免疫反应的推动下，肥胖/代谢等因素 功能障碍与更严重的哮喘有关。因此，“肥胖哮喘”的内型与 频繁的哮喘恶化，从Th2主导的炎症转变为Th17主导的炎症 个人资料，以及明显的女性偏见。我们对肥胖性哮喘发病机制的一个主要认识差距是 由于常见的肥胖小鼠模型的缺陷；标准的高脂饮食(HFD)喂养的小鼠模型有 不能在女性中引起广泛的体重增加和代谢障碍(与人类肥胖有关) 老鼠-这是一个主要的缺点，因为在肥胖的哮喘内型中观察到了女性偏见。重要的是，我们的 研究小组已经确定，在C57BL/6小鼠处于代谢温度的情况下喂养HFD 体内平衡(温度(TN)；30-33°C)促进严重肥胖和代谢功能障碍 雌性老鼠。使用该模型的初步数据表明，过敏原激发的肥胖哮喘小鼠 证明：(1)与瘦哮喘对照组相比，哮喘预后更差，(2)远离Th2 炎症到促炎状态(Th17或Th2/Th17)，以及(3)明显的女性偏见。类似 在雄鼠身上没有观察到这种变化。这些数据表明，TN存在肥胖的雌性哮喘小鼠 建立人类肥胖哮喘内型模型。重要的是，肥胖的哮喘雌性小鼠表现出了深刻的 肺中产生IL-17A细胞的频率增加，特别是粘膜相关的不变T细胞 (MAIT)细胞。MAIT细胞是一种先天的T细胞，在肺、肝和脂肪组织中大量存在。尽管被认为 在瘦性哮喘模型中的保护作用，在肥胖、肝脏和脂肪组织中切换到促炎状态 并导致代谢功能障碍。在这个应用中，我们假设，在肥胖中，肝脏和脂肪 组织MAIT细胞变成促炎细胞，并被许可迁移到肺，在那里它们驱动 雌性肥胖-哮喘小鼠的严重哮喘后果。这一假设将在两个具体的 目标。目的1：明确肥胖者组织内MAIT细胞的功能和表型差异 患有哮喘的女性。我们将研究MAIT细胞在肺和肺组织中的聚集和细胞因子的表达模式 代谢组织(肝脏、白色脂肪组织)随着时间的推移，量化不同的MAIT细胞对TCR- 依赖和独立的信号，并执行肺MAIT细胞的无偏转录图谱 瘦而肥胖的哮喘雌性小鼠。目的2：确定MAIT细胞在哮喘转归中的作用 肥胖的雌性老鼠。我们将用MAIT细胞抑制配体或过继疗法治疗瘦小和肥胖的哮喘小鼠 移植瘦小或肥胖哮喘小鼠的肺MAIT细胞并评估其必要性和充分性 哮喘表型。完成拟议的研究将有助于更好地了解这些机制 与“肥胖性哮喘”和MAIT细胞生物学相关的独特临床参数。

ABSTRACT Asthma is an inflammatory lung disease that affects >300 million people worldwide. Although mild asthma is driven by a Th2-associated, eosinophil-dominated immune response, factors such as obesity/metabolic dysfunction are associated with more severe asthma. Thus, the “obese asthma” endotype is associated with frequent asthma exacerbations, a shift away from Th2-dominated inflammation towards a Th17-dominated profile, and a marked female bias. A major gap in our understanding of mechanisms driving obese asthma is due to deficiencies in common mouse models of obesity; standard high-fat diet (HFD)-fed mouse models are unable to induce extensive weight gain and metabolic dysfunction (associated with obesity in humans) in female mice - a major shortcoming given the female bias observed in the obese asthma endotype. Importantly, our group has determined that HFD feeding of C57BL/6 mice housed at a temperature in which they are at metabolic homeostasis (thermoneutral temperature (TN); 30-33°C) promotes severe obesity and metabolic dysfunction in female mice. Preliminary data using this model demonstrate that allergen-challenged obese asthmatic mice demonstrate: (1) worse asthmatic outcomes compared to lean asthma controls, (2) a shift away from Th2 inflammation to a pro-inflammatory profile (Th17 or Th2/Th17), and (3) a pronounced female bias. Similar changes are NOT observed in male mice. These data suggest that TN housed obese female asthmatic mice model the human obese asthma endotype. Importantly, obese asthmatic female mice demonstrated a profound increase in the frequency of IL-17A-producing cells in the lungs, particularly mucosal-associated invariant T (MAIT) cells. MAIT cells are innate-like T cells abundant in lungs, liver, and adipose tissue. Although considered protective in models of lean asthma, in obesity, liver and adipose tissue MAIT switch to a pro-inflammatory state and contribute to metabolic dysfunction. In this application we hypothesize that, in obesity, liver and adipose tissue MAIT cells become pro-inflammatory and are licensed to migrate to the lung, where they drive severe asthma outcomes in female obese-asthmatic mice. This hypothesis will be tested in two Specific Aims. Aim 1: To define the functional and phenotypic differences of tissue resident MAIT cells in obese asthmatic females. We will examine patterns of MAIT cell accumulation and cytokine expression in lung and metabolic tissue (liver, white adipose tissue) over time, quantify differential MAIT cell responsiveness to TCR- dependent and independent signals, and perform non-biased transcriptional profiling of lung MAIT cells from lean and obese asthmatic female mice. Aim 2: To determine the role of MAIT cells in asthma outcomes in obese female mice. We will treat lean and obese asthmatic mice with a MAIT cell inhibitory ligand or adoptively transfer lung MAIT cells from lean or obese asthmatic mice and assess their necessity and sufficiency on the asthma phenotype. Completion of the proposed studies will facilitate a better understanding of the mechanisms underlying the unique clinical parameters associated with “obese asthma” and MAIT cell biology.