Regulation of T cell responses to allergens and environmental microbes

摘要哮喘是一种慢性肺部疾病，会使气道发炎/变窄。慢性变应性炎症 主要由辅助性T细胞2（Th 2）对空气传播的过敏原的异常激活/扩增介导。 有趣的是，大多数Th 2型哮喘患者在年轻时就出现了首次症状，这表明， 成人哮喘的结果在幼儿期确定。近几十年来，发病率、发病率和 儿童过敏性哮喘的死亡率和相关费用在世界范围内不断增加，特别是在 工业化国家;而不是由于遗传背景，但主要是因为 环境和生活方式风险因素。“卫生假说”认为， 粉尘含有高水平的细菌内毒素（LPS）和其他微生物衍生化合物， 年龄小是哮喘发病率增加的主要原因之一。然而，没有精确的机制， 已经描述了婴儿期对高LPS环境的这种独特需求。我们已经发表 暴露于过敏原诱导过敏原特异性Th 2细胞应答;但暴露于含有 相对低剂量的LPS阻止了Th 2细胞的初始引发和随后的Th 2细胞的发育。 介导的成年小鼠而非幼年小鼠气道中的炎症反应。这些数据显示，成年人和 幼年小鼠对LPS的反应具有不同的阈值，因此，需要相对较高剂量的LPS， 预防幼鼠的Th 2细胞反应和过敏性炎症。从机制上讲，我们发现， 而婴儿常规树突状细胞（cDCs）抑制过敏性Th 2反应的能力受损 低剂量内毒素致敏后。重要的是，我们的新数据表明，为了有效抑制 过敏性Th 2细胞活性，cDC的功能性活化和活化T细胞的反应性， 取决于几种细胞因子的协调作用（即，TNFα、IL-12、IL-18、IFNγ和IL-6）。此外，本发明还 我们的数据表明，第一个感受LPS并产生细胞因子以许可cDCs功能的细胞 是单核细胞衍生的树突状细胞（moDC）。最后，我们的数据表明，母亲的牛奶为基础的饮食， 调节moDCs的分化和功能，最终导致向Th 2细胞偏好的转变 在婴儿时期。因此，我们假设在低剂量LPS/过敏原致敏反应中，moDCs启动了一种新的免疫应答机制。 细胞因子级联反应，最终介导成人Th 2驱动的过敏性炎症的抑制。在 婴儿，否则，这条道路被自然饮食的影响所抑制;使他们更容易受到影响。 过敏性疾病在这个建议中，我们将测试特定的细胞因子如何调节T辅助细胞程序， 过敏原以及婴儿饮食和微生物暴露如何不同地影响这一过程。我们相信 这项建议的实验将大大有助于我们了解饮食环境如何 相互作用有助于儿童过敏性致敏的发展，最终将揭示新的 关于预防儿童哮喘/过敏的潜在目标的信息。

Summary. Asthma is a chronic lung disease that inflames/narrows the airways. Chronic allergic inflammation is primarily mediated by the aberrant activation/expansion of T-helper 2 (Th2) cells to airborne allergens. Interestingly, most people with Th2 asthma experience their first symptoms at a young age, suggesting that outcomes in adult asthma are determined in early childhood. In recent decades, incidence, morbidity, and mortality of pediatric allergic asthma and associated cost have been increasing worldwide, specifically among industrialized countries; and not due to the genetic background, but mainly because of the effect of environmental and lifestyle risk factors. The "hygiene hypothesis" proposes that the decreased exposure to dust containing high levels of bacterial endotoxin (LPS) and other microorganism-derived compounds at a very early age is one of the main drivers of the increasing incidence of asthma. However, no precise mechanism for this unique requirement for a high-LPS environment during infancy had been delineated. We have published that exposure to allergen induced allergen-specific Th2 cell responses; but exposure to allergen containing relatively low-doses of LPS prevented the initial priming of Th2 cells and development of subsequent Th2 cell- mediated inflammatory response in the airways of adult but not infant mice. These data show that adult and infant mice respond to LPS with different thresholds and, thus, relatively higher-doses of LPS are required to prevent Th2 cell responses and allergic inflammation in infant mice. Mechanistically, we found that unlike adult counterparts, infant conventional dendritic cells (cDCs) had impaired ability to suppress allergic-Th2 responses upon low-dose endotoxin sensitization. Importantly, our new data suggest that for the effective suppression of allergic Th2 cell activity, both the functional activation of cDCs, and the responsiveness of activated T cells are contingent on the coordinated actions of several cytokines (i.e., TNFα, IL-12, IL-18, IFNγ, and IL-6). Further, our data suggest that the first cells that sense LPS and produce cytokines to license the function of the cDCs are monocyte-derived dendritic cells (moDCs). Finally, our data show that the mother's milk-based diet conditions the differentiation and function of moDCs, which ultimately leads to a shift toward Th2 cell bias during infancy. Thus, we hypothesize that in response to low-dose LPS/allergen sensitization, moDCs initiate a cascade of cytokines, which ultimately mediate the suppression of Th2-driven allergic inflammation in adults. In infants, otherwise, this path is suppressed by the influence of the natural diet; rendering them more susceptible to allergy disease. In this proposal, we will test how specific cytokines modulate T helper cell program to allergens and how the infant diet and microbial exposure differentially affects this process. We believe the experiments in this proposal will significantly contribute to our understanding of how diet-environment interactions contribute to the development of allergic sensitization in children and ultimately will reveal new information about potential targets for prevention of asthma/allergies in children.