A protective role for gamma delta T cells in respiratory infection

 描述(申请人提供)：2岁以下儿童是呼吸道感染(包括流感)后严重发病率和死亡率的高危群体。除了缺乏多年的免疫学经验和记忆反应外，新生儿和婴儿的免疫系统与成人在质量和数量上都有其他区别。在这项提案中，我们将 研究γδT细胞在为幼儿提供保护方面的特殊作用。这些细胞既具有先天免疫的特点，也具有适应性免疫的特点。γδT细胞在流感感染过程中还没有得到广泛的研究，这些细胞保护呼吸道粘膜的机制也不清楚。已发表的报告表明，在促进炎症方面的作用相对有限；然而，这些研究是在成年动物身上进行的。我们的初步数据表明，γδT细胞在流感感染后新生儿的生存中发挥着必要的作用，这可能是由于其他免疫效应器的不成熟所致。这种保护依赖于γδT细胞诱导的IL-33的产生。IL-33调节ILC2的活性和嗜酸性粒细胞的募集，其中BOT在恢复上皮完整性方面发挥作用。这一建议的中心假设是TATγδT细胞启动一种免疫级联反应，通过招募和激活ILC2和嗜酸性粒细胞来提高新生儿流感感染的存活率。我们的三个目标测试了特定的假设：1)γδT细胞通过分泌IL-17促进新生小鼠流感感染后的存活，这导致肺上皮细胞产生IL-33；2)γδT细胞激活下游的IL-33导致ILC2激活和嗜酸性粒细胞聚集，这是新生儿肺功能恢复所必需的；以及3)类似的调节网络在人类中运行，我们将使用有价值的临床人类分离库进行测试。这些实验将定义一种在非常年轻的儿童中运行的独特的保护机制，为γδT细胞和IL-17产生的II型免疫模式上游建立一个作用 提供预防流感相关疾病的保护。

 DESCRIPTION (provided by applicant): Children under 2 are a high risk group for severe morbidity and mortality after respiratory infections, including influenza. In addition to lacking years of immunological experience and memory responses, neonatal and infant immune systems have other qualitative and quantitative distinctions from adults. In this proposal, we will examine a special role for γδ T cells in providing protection in the very young. These cells possess features of both the innate and adaptive arms of immunity. γδ T cells have not been extensively studied during influenza infection, and the mechanisms by which these cells protect the respiratory mucosa are not known. Published reports suggest a relatively limited role in promoting inflammation; however, these studies were done in adult animals. Our preliminary data indicate that γδ T cells play a necessary role in the survival of neonates after influenza infection, perhaps due to the immaturity of other immune effectors. This protection depends on γδ T cell-induced IL-33 production. IL-33 regulates ILC2 activity and eosinophil recruitment, bot of which play roles in restoring epithelial integrity. The central hypothesis of this proposal is tat γδ T cells initiate an immune cascade that promotes survival in neonatal influenza infection via the recruitment and activation of ILC2s and eosinophils. Our three aims test the specific hypotheses that 1) γδ T cell promote survival after influenza infection in neonatal mice by secreting IL-17, which leads to the induction of IL-33 from lung epithelial cells, 2) that IL-33 downstream of γδ T cell activation leads to ILC2 activation and eosinophil accumulation, which are necessary for recovery of lung function in neonates, and 3) that a similar regulatory network is operating in humans, which we will test using a valuable repository of clinical human isolates. These experiments will define a distinct protective mechanism operating in the very young, establishing a role for γδ T cells and IL-17 production upstream of a Type II immune profile that provides protection from influenza- associated disease.