Natural Th17 cells in allergic airway disease

描述（由申请方提供）：IL-17是对许多病原体和过敏原的免疫应答的重要组分。IL-17的常见来源是CD 4 + T辅助17（Th 17）细胞。这些细胞从幼稚的CD 4细胞分化为外周部位的IL-17产生细胞，并被称为常规Th 17细胞（cTh 17）。最近，我们和其他人发现了另一群产生IL-17的CD 4 +TCR + T细胞，它们在胸腺中发育期间分化成IL-17分泌细胞，然后迁移到外周。这些T细胞被称为“天然”Th 17（nTh 17）细胞，存在于人类和小鼠中。最近的研究结果表明，nTh 17细胞迁移到外周部位，包括肺，并进一步表明这些细胞可能在包括哮喘在内的病理条件下很重要。虽然nTh 17和cTh 17细胞具有相似的细胞因子谱，但我们的初步数据表明，nTh 17 T细胞不仅仅是在胸腺而不是外周中引发IL-17产生的CD 4 T细胞，而是在免疫系统中具有特定作用的根本区别。考虑到IL-17在免疫应答早期的重要性，我们推测在选择过程中，胸腺细胞的亚群被引导以产生IL-17，以确保产生能够快速释放IL-17的群体。直到最近，还无法区分nTh 17和cTh 17细胞的生物学作用。然而，我们已经发现nTh 17和cTh 17细胞利用Akt/mTOR/HIF信号通路的不同组分来产生IL-17。使用精心设计的nTh 17或cTh 17细胞发育缺陷的小鼠，我们有独特的机会来确定nTh 17与cTh 17细胞在气道疾病中的作用。该提案的重点是了解nTh 17细胞在其发育过程中利用的分子信号如何决定其在次级TCR诱导的活化后的功能（目的1）;以及利用nTh 17和cTh 17 T细胞的不同发育要求来确定它们是否在充分表征的哮喘小鼠模型中具有不同的作用（目的2）。在目标1中，我们将使用缺乏通过该途径发出信号的能力的小鼠来确定HIF 1 <$在nTh 17细胞发育和功能中的作用。在目标2中，我们将利用我们的烟曲霉提取物诱导的哮喘的良好表征的模型来确定nTh 17细胞对哮喘的贡献。

DESCRIPTION (provided by applicant): IL-17 is an essential component of the immune response to many pathogens and allergens. A common source of IL-17 is CD4+ T helper 17 (Th17) cells. These cells differentiate from na¿ve CD4 cells into IL-17 producing cells at peripheral sites and are termed, conventional Th17 cells (cTh17). Recently, we and others discovered another population of IL-17 producing CD4+TCR¿¿+ T cells that differentiate into IL-17 secreting cells during their development in the thymus, prior to their migration into the periphery. These T cells are termed "natural" Th17 (nTh17) cells and are present in humans as well as mice. Recent findings reveal that nTh17 cells migrate to peripheral sites, including the lung, and further suggest these cells may be important in pathological conditions including asthma. Although nTh17 and cTh17 cells have similar cytokine profiles, our preliminary data suggest that nTh17 T cells are not simply CD4 T cells that are primed for IL-17 production in the thymus instead of the periphery, but are fundamentally distinct with specific roles in the immune system. Given the importance of IL-17 early in immune responses, we speculate that during selection, a subset of thymocytes is directed to make IL-17 to ensure the generation of a population capable of rapid IL-17 release. Until recently, it was not possible to distinguish the biologic role of nTh17 and cTh17 cells. However, we have discovered that nTh17 and cTh17 cells utilize different components of the Akt/mTOR/HIF signaling pathway for IL-17 production. Using carefully designed mice with defects in either nTh17 or cTh17 cell development we have the unique opportunity to determine the contribution of nTh17 versus cTh17 cells in airway disease. This proposal is focused on understanding how the molecular signals utilized by nTh17 cells during their development dictate their function following secondary TCR induced activation (Aim 1); and on exploiting the distinct developmental requirements of nTh17 and cTh17 T cells to establish whether they possess distinct roles in a well characterized mouse model of asthma ( Aim 2). In Aim 1 we will determine the role of HIF1¿ in nTh17 cells development and function using mice lacking the ability to signal through this pathway. In Aim 2, we will take advantage of our well-characterized model of Aspergillus fumigatus extract induced asthma to determine the contribution of nTh17 cells to asthma.