Imprinting of Lung-Resident T Cell Memory

描述（由申请人提供）：肺部是病原体进入的常见门户，呼吸道病原体如流感和结核分枝杆菌是主要的全球健康问题。因此，肺疫苗学的一个主要挑战是开发一种在肺中提供持久和持久免疫的方法。解决这个问题的一种方法是开发旨在促进肺部驻留T细胞记忆产生的疫苗。在动物模型和人类研究中，记忆T细胞已被证明在流感攻击后显著降低病毒载量，导致更快的病毒清除和降低疾病严重程度。这些研究和其他研究的一个关键发现是，记忆T细胞的保护功效与流感攻击时肺中存在的记忆T细胞数量直接相关;随着肺中记忆T细胞数量的下降，对病原体攻击的保护也是如此。因此，产生驻留在肺实质和肺气道中的记忆T细胞是增强对流感或其他呼吸道病原体的细胞免疫的有希望的策略。然而，我们仍然缺乏对如何在感染部位（肺部）产生和维持组织驻留记忆T细胞的基本了解，在那里它们具有独特的位置，可以快速响应呼吸道感染。此外，我们不知道肺驻留记忆细胞用于提供保护性免疫的效应机制。为了提高对呼吸道病原体的细胞免疫力，我们必须首先更好地理解肺气道和肺实质中组织驻留记忆T细胞的产生、维持和回忆的机制。这就是目前提案的目标。

DESCRIPTION (provided by applicant): The lung is a common portal of pathogen entry, and respiratory pathogen such as influenza and Mycobacterium tuberculosis are major global health problems. Thus, a major challenge of pulmonary vaccinology is to develop an approach that will provide long-lasting and durable immunity in the lung. One approach to this problem is the development of vaccines designed to promote the generation of lung-resident T cell memory. In animal models and human studies, memory T cells have been shown to significantly reduce viral loads after influenza challenge, leading to faster viral clearance and decreased disease severity. A key finding from these and other studies was that the protective efficacy of memory T cells directly correlated with the number of memory T cells present in the lung at the time of influenza challenge; as the number memory T cells in the lung declined, so did protection from pathogen challenge. Therefore, generating memory T cells that reside in the lung parenchyma and lung airways is a promising strategy to enhance cellular immunty to influenza or other respiratory pathogens. However, we still lack a basic understanding of how to generate and maintain tissue-resident memory T cells at the site of infection (the lung) where they are uniquely positioned to rapidly respond to a respiratory infection. Furthermore, we do not know the effector mechanisms that lung resident-memory cells use to provide protecitive immuniy. To improve cellular immunity against respiratory pathogens we must first acquire a better understanding of the mechanism(s) that underlie the generation, maintenance, and recall of tissue-resident memory T cells in the lung airways and lung parenchyma. This is the goal of the current proposal.