Natural Th17 cells in allergic airway disease

描述(由申请人提供)：IL-17是许多病原体和过敏原免疫反应的重要组成部分。IL-17的一个常见来源是CD4+T辅助17(Th17)细胞。这些细胞在外周部位从原始的CD4细胞分化为产生IL-17的细胞，被称为常规Th17细胞(CTh17)。最近，我们和其他人发现了另一群产生IL-17的CD4+TCR？+T细胞，它们在胸腺发育过程中分化为IL-17分泌细胞，然后迁移到外周。这些T细胞被称为“天然”Th17(NTh17)细胞，在人类和小鼠中都存在。最近的发现显示，nTh17细胞迁移到包括肺在内的周围部位，进一步表明这些细胞在包括哮喘在内的病理条件下可能是重要的。尽管nTh17和cTh17细胞具有相似的细胞因子谱，但我们的初步数据表明，nTh17 T细胞不仅仅是准备在胸腺而不是外周产生IL-17的CD4T细胞，而是在免疫系统中扮演特定角色的根本不同的细胞。鉴于IL-17在早期免疫反应中的重要性，我们推测在选择过程中，胸腺细胞的一部分被指示产生IL-17，以确保产生能够快速释放IL-17的种群。直到最近，还不可能区分nTh17和cTh17细胞的生物学作用。然而，我们发现nTh17和cTh17细胞利用Akt/mTOR/HIF信号通路中不同的成分来产生IL-17。利用精心设计的nTh17或cTh17细胞发育缺陷的小鼠，我们有独特的机会来确定nTh17细胞与cTh17细胞在呼吸道疾病中的作用。这项建议侧重于了解nTh17细胞在发育过程中利用的分子信号如何决定其在TCR诱导二次激活后的功能(目标1)；以及利用nTh17和cTh17 T细胞的不同发育需求来确定它们在具有良好特征的哮喘小鼠模型中是否具有不同的作用(目标2)。在目标1中，我们将利用缺乏通过这一途径发出信号的小鼠来确定HIF1在nTh17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发哮喘的模型来确定nTh17细胞在哮喘中的作用。

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.