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: 9113835
• 负责人: Paul G. Thomas
• 金额: $ 45.84万
• 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/9113835
• 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; Infant; Infection; Inflammation; Influenza; 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; 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 Activation; T-Cell Receptor; T-Lymphocyte; Testing; Work; Wound Healing; arm; base; cohort; cytokine; eosinophil; experience; high risk; insight; mature animal; mortality; mouse model; neonate; neutrophil; novel; pathogen; predict clinical outcome; public health relevance; repository; research study; respiratory; response; tissue repair

 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（由适用提供）：2岁以下的儿童是呼吸道感染后严重发病和死亡率的高风险组，包括影响力。除了缺乏多年的免疫经验和记忆反应外，新生儿和婴儿免疫系统还具有成年人的其他定性和定量破坏。在此提案中，我们将 考察γδT细胞在非常年轻的保护中提供保护的特殊作用。这些细胞具有免疫的先天和适应性臂的特征。 γδT细胞在影响力感染期间尚未广泛研究，并且这些细胞保护呼吸粘膜的机制尚不清楚。发表的报告表明，在促进感染中起着相对有限的作用。但是，这些研究是在成年动物中进行的。我们的初步数据表明γδT细胞在影响感染后的新生儿的存活中起着必要的作用，这可能是由于其他免疫作用的不可分割所致。该保护取决于γδT细胞诱导的IL-33产生。 IL-33调节ILC2活性和嗜酸性粒细胞的募集，其机器人在恢复上皮完整性中起着作用。该提案的中心假设是TATγδT细胞启动了一种免疫果皮，通过募集和激活ILC2和嗜酸性粒细胞来促进新生儿影响感染的生存。我们的三个目的测试了特定的假设，即1）γδT细胞通过分泌IL-17在新生小鼠中促进生存，这导致从肺上皮细胞中诱导IL-33，2）IL-33γδT细胞活化的下游会导致ILC2活化和EOSOSINOPIL的作用，这是IL-33的下游，这是必不可少的。监管网络正在人类中运行，我们将使用临床人分离株的宝贵存储库进行测试。这些实验将定义在非常年轻的情况下运行的独特保护机制，从而确立了γδT细胞的作用，并在II型免疫概谱上游的IL-17产生中发挥了作用， 提供免受影响力相关疾病的保护。