A protective role for gamma delta T cells in respiratory infection

γδT 细胞在呼吸道感染中的保护作用

• 批准号: 9234456
• 负责人: Paul G. Thomas
• 金额: $ 45.45万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234456
• 关键词: Adult; Animal Model; Animals; Antigens; Cells; Child; Classification; Clinical; Comparative Biology; Data; Disease; Elements; Epithelial; Epithelial Cells; Family; Fostering; Genetic; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Infant; Infection; Inflammation; Influenza; Innate Immune Response; Interferon Type II; Interleukin-13; Interleukin-17; Interleukin-5; Kinetics; Ligation; Lung; Lymphoid Cell; Memory; Morbidity - disease rate; Mucous Membrane; Mus; Neonatal; Outcome; Pathway interactions; Patients; Peptides; Peripheral; Play; Population; Predisposition; Production; Publishing; Receptor Cell; Recovery; Recruitment Activity; Reporting; Resources; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Respiratory physiology; Respiratory tract structure; Role; Sampling; Source; Streptococcus pneumoniae; Surface; T-Cell Receptor; T-Lymphocyte; Testing; Work; Wound Healing; arm; base; cohort; cytokine; eosinophil; experience; experimental study; high risk population; insight; mature animal; mortality; mouse model; neonate; neutrophil; novel; pathogen; predict clinical outcome; public health relevance; repository; respiratory; response; tissue repair; γδ T cells

 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.

 描述（由申请人提供）：2岁以下儿童是呼吸道感染（包括流感）后发生严重发病和死亡的高危人群。除了缺乏多年的免疫经验和记忆反应之外，新生儿和婴儿的免疫系统还存在其他定性和定量的差异。在这项提案中，我们将由成人提出。 检查 γδ T 细胞在为幼儿提供保护方面的特殊作用。这些细胞具有先天性和适应性免疫的特征，但尚未主要在流感感染过程中进行研究，以及这些细胞的保护机制。已发表的报告表明，其在促进炎症方面的作用相对有限；但是，我们的初步数据表明，γδ T 细胞在流感感染后的新生儿生存中可能发挥着必要的作用。由于这种保护依赖于 γδ T 细胞诱导的 IL-33 调节 ILC2 活性和嗜酸性粒细胞募集，其在恢复上皮完整性中发挥作用。细胞启动免疫级联反应，通过 ILC2 和嗜酸性粒细胞的募集和激活来促进新生儿流感感染的存活。我们的三个目标测试了以下具体假设：1) γδ T 细胞通过分泌 IL-17 促进新生小鼠流感感染后的存活，从而导致肺上皮细胞诱导 IL-33，2）γδ T 细胞激活下游的 IL-33 导致 ILC2 激活和嗜酸性粒细胞积累，这对于新生儿肺功能的恢复是必要的，并且3）类似的调节网络正在人类中运行，我们将使用有价值的临床人类分离物库进行测试这些实验将定义一个独特的。保护机制在非常年轻的时候发挥作用，在 II 型免疫谱上游建立了 γδ T 细胞和 IL-17 产生的作用， 提供针对流感相关疾病的保护。