Optimizing functional synergies between local and systemic memory CD4 T cell responses to influenza

摘要/摘要 针对甲型流感病毒（IAV）的保护性记忆CD4 T细胞应答涉及多种细胞类型 具有独特的特征。异质性的一个新出现的轴是肺组织-居民之间的划分。 记忆细胞（TRM）和通过次级淋巴器官循环的常规记忆细胞。大多数研究 迄今为止，在回忆过程中， 应答然而，我们的初步研究支持区域和系统之间的协同作用的概念， 记忆细胞是非常有效的CD4 T细胞应答的一个重要的和未表征的方面。我们的工作还 表明这种综合反应可以优化，以改善病毒控制和减少 通过促进TRM与常规记忆CD4细胞中的不同功能来改善免疫病理学。这 该提案将为疫苗如何最大限度地发挥地方和地方之间的协同作用提供新的机制见解。 系统性CD4记忆细胞，以改善疫苗诱导的抗IAV保护。 我们将优化模型，以重建具有良好表征的肺TRM的单独群体的幼稚小鼠 和/或由IAV引发的常规记忆CD4细胞。该实验系统将有助于对 TRM反应如何影响系统记忆CD4的再激活和随后的反应参数 细胞感染IAV。我们的模型还将允许调制的数量和功能的能力， 每个存储器隔室内的单元，以便识别保护的唯一子集特定相关性。 我们还将特异性地耗尽IAV免疫小鼠中的CD4 TRM，从而允许进一步表征局部和局部TRM。 在完整的接种疫苗的小鼠中，在异亚型感染期间的系统记忆CD4协同作用。 在目标1中，我们将检验以下假设：在IAV感染的最初几天内，肺CD4 TRM活化 增加次级淋巴器官中抗原呈递的效率，导致更快地回忆 传统的记忆CD4细胞。我们还将确定是否TRM减少传统内存的大小 通过早期控制肺部的病毒滴度和炎症反应。在目标2中，我们将确定 整合记忆CD4应答如何影响IAV清除和附带损害的关键参数 与单独用任一记忆子集重建的小鼠相比。最后，我们将确定协同CD4 通过将原型T-bet依赖性Th1编程仅限制在 TRM子集。这项工作将提供一个机制框架，以提高CD4 T细胞依赖的保护， IAV和其他病原体，并优化创新的实验系统，以促进未来的发现。

Summary/Abstract Protective memory CD4 T cell responses against influenza A virus (IAV) involve a diverse array of cell types with unique characteristics. An emerging axis of heterogeneity is the division between lung tissue-resident memory (TRM) and conventional memory cells that circulate through secondary lymphoid organs. Most studies to date have focused on characterizing the anti-viral activities of these subsets in isolation during recall responses. Our preliminary studies, however, support the concept that synergies between regional and systemic memory cells are a vital and uncharacterized aspect of highly effective CD4 T cell responses. Our work also indicates that such integrated responses can be optimized to improve viral control and to reduce immunopathology by promoting different functions in TRM versus in conventional memory CD4 cells. This proposal will provide novel mechanistic insight into how vaccines can maximize synergies between local and systemic CD4 memory cells to improve vaccine-induced protection against IAV. We will optimize models to reconstitute naive mice with separate populations of well characterized lung TRM and/or conventional memory CD4 cells primed by IAV. This experimental system will facilitate clear analysis of how TRM responses impact the re-activation and subsequent response parameters of systemic memory CD4 cells upon IAV infection. Our models will also allow for modulation of the numbers and functional capacities of the cells within each memory compartment in order to identify unique subset-specific correlates of protection. We will also specifically deplete CD4 TRM in IAV-immune mice, thus allowing further characterization of local and systemic memory CD4 synergy during heterosubtypic infection in intact, vaccinated mice. In Aim 1, we will test the hypothesis that lung CD4 TRM activation within the first few days of IAV infection increases efficiency of antigen presentation in secondary lymphoid organs, leading to the more rapid recall of conventional memory CD4 cells. We will also determine if TRM reduce the magnitude of conventional memory responses through their earlier control of viral titers and inflammation in the lung. In Aim 2, we will determine how the integrated memory CD4 response affects key parameters of IAV clearance and collateral damage versus in mice reconstituted with either memory subset alone. Finally, we will determine if synergistic CD4 protection against IAV can be improved by restricting prototypical T-bet-dependent Th1 programming to only the TRM subset. This work will provide a mechanistic framework to improve CD4 T cell-dependent protection against IAV and other pathogens and optimize innovative experimental systems to facilitate future discovery.