Development of Localized T Cell Immunity in Pediatric Respiratory Tract Infection

7.项目总结摘要 康纳斯医生是一名儿科重症监护内科医生，科学家正在研究 婴幼儿的保护性适应性免疫反应，特别是在病毒感染的背景下 呼吸道感染(VRTI)。VRTI在早期生活中无处不在，通常代表第一大 对发育中的免疫系统的挑战。大多数儿童不需要医疗就能清除感染。 注意，VRTI的严重疾病是导致呼吸衰竭的主要原因 婴儿期机械通风。重要的是，早期生命免疫反应与 感染和环境暴露会导致晚年肺功能的改变。AS 早期生命中的免疫反应是未来抵御病原体的形成，早期的异常反应 生活可能会产生持久的影响。需要将T细胞分化为效应器和记忆亚群 病毒清除和保护性免疫的建立。小鼠模型已经证明了 驻留记忆T细胞(Trm)调节最佳保护。然而，新生的小鼠T细胞显示 转录上不同的反应有利于产生终末分化的效应性T细胞 建立Trm.对人体组织的研究表明，组织中的T细胞主要是调节性的 (Treg)在婴儿时期的自然界中，几乎没有Trm。重要的是，VRTI期间的局部T细胞反应与 与婴儿和儿童的疾病严重性有关。T细胞亚群在急性感染中的保护作用 而导致建立长寿命记忆子集的机制仍未确定 早年的生活。我们的中心假设是，对VRTI的保护依赖于局部适应性免疫反应 婴儿期形成期异常的免疫反应与临床严重程度有关。 这项建议的目的是1)确定T细胞在早期生命中分化的途径和2)确定T细胞在生命早期的作用 VRTI致小儿急性呼吸窘迫综合征(PARDS)T细胞亚群的变化这份职业 发展奖代表着实现候选人过渡到 独立研究人员专注于适应性免疫反应和危重疾病的翻译研究 孩子们。应聘者目前所提供的学术、指导、培训和临床机会 环境为成功完成这一项目和康纳斯博士提供了完美的场所 实现他的目标。

7. PROJECT SUMMARY ABSTRACT Dr. Connors is a Pediatric Critical Care Physician Scientist investigating the generation and establishment of protective adaptive immune responses in infants and young children, particularly in the context of viral respiratory tract infections (VRTI). VRTI are ubiquitous in early life and commonly represent the first major challenge to the developing immune system. The majority of children clear infection without requiring medical attention, however severe disease from VRTI is the leading cause of respiratory failure necessitating mechanical ventilation during infancy. Importantly, associations between early life immune responses to infections and environmental exposures have been made to alterations in pulmonary function in later life. As immune responses in early life are formative for future protection from pathogens, aberrant responses in early life can have enduring repercussions. Differentiation of T cells to effector and memory subsets is required for viral clearance and establishment of protective immunity. Mouse models have demonstrated the importance of resident memory T cells (Trm) in mediating optimal protection. However neonatal mice T cells demonstrate transcriptionally distinct responses favoring the generation of terminally differentiated effector T cells over the establishment of Trm. Studies of human tissue have shown that T cells in tissue are predominately regulatory (Treg) in nature during infancy with few Trm. Importantly local T cell responses during VRTI are associated with disease severity in infants and children. The T cell subsets mediating protection during acute infection and the mechanisms leading to the establishment of long lived memory subsets remains uncharacterized in early life. Our central hypothesis is that protection from VRTI relies on the local adaptive immune response and aberrant immune responses during the formative window of infancy are associated with clinical severity. The aims of this proposal are 1) Determine pathways for T cell differentiation in early life and 2) Define the role of T cell subsets in VRTI induced Pediatric Acute Respiratory Distress Syndrome (PARDS). This career development award represents a crucial step in attaining the candidate’s long-term goal of transitioning to an independent researcher focused on translational studies of adaptive immune responses and critical illness in children. The academic, mentoring, training, and clinical opportunities afforded by the candidate’s current environment provide the perfect venues for successful completion of this project and for Dr. Connors to achieve his goal.