Regulation of T cell responses to allergens and environmental microbes

总结。哮喘是一种慢性肺部疾病，会使呼吸道发炎/变窄。慢性变态反应性炎症 主要由T辅助细胞2(Th2)细胞对空气传播的过敏原的异常激活/扩张所介导。 有趣的是，大多数患有Th2型哮喘的人在很小的时候就出现了第一个症状，这表明 成人哮喘的结局是在儿童早期决定的。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一直在上升，特别是在 工业化国家；并不是由于遗传背景，而主要是因为 环境和生活方式风险因素。“卫生假说”提出，减少接触 粉尘中含有高水平的细菌内毒素(LPS)和其他微生物衍生的化合物 早年是哮喘发病率上升的主要驱动因素之一。然而，没有精确的机制来实现 对婴儿期高内毒素环境的这一独特要求已经被描绘出来。我们已经出版了 暴露于过敏原可诱导过敏原特异的Th2细胞反应；但暴露于含有 相对较低剂量的内毒素阻止了Th2细胞的初始启动和随后Th2细胞的发展。 成年小鼠呼吸道的炎症反应，而不是幼鼠的炎症反应。这些数据表明，成年人和 幼鼠对内毒素的反应阈值不同，因此，需要相对较高剂量的内毒素来 预防幼鼠Th2细胞反应和变态反应性炎症。从机制上讲，我们发现与成人不同 与之对应的是，婴儿常规树突状细胞(CDCs)抑制过敏-Th2反应的能力受损 小剂量内毒素致敏。重要的是，我们的新数据表明，为了有效地抑制 过敏性Th2细胞活性，包括CDC的功能激活和激活的T细胞的反应性 取决于几种细胞因子(即肿瘤坏死因子α、IL-12、IL-18、干扰素γ和IL-6)的协同作用。此外， 我们的数据表明，第一批感知内毒素并产生细胞因子的细胞可以许可CDC的功能 是单核细胞来源的树突状细胞(MoDC)。最后，我们的数据显示，母亲以牛奶为基础的饮食 调节moDC的分化和功能，最终导致偏向Th2细胞 在婴儿期。因此，我们假设，在低剂量的内毒素/变应原致敏反应中，moDC启动了一种 细胞因子的级联，最终介导抑制Th2驱动的成人过敏性炎症。在……里面 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 对于过敏性疾病。在这个方案中，我们将测试特定的细胞因子如何调节T辅助细胞程序来 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 这一提议中的实验将极大地有助于我们理解饮食环境 相互作用有助于儿童过敏反应的发展，并最终将揭示新的 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.