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CD4T细胞反应涉及多种细胞类型 具有独特的特点。异质性的一个新轴心是肺组织驻留在 记忆(TRM)和通过次级淋巴器官循环的常规记忆细胞。大多数研究 到目前为止，他们的重点是在召回过程中孤立地表征这些亚群的抗病毒活性 回应。然而，我们的初步研究支持这样一个概念，即区域和系统之间的协同作用 记忆细胞是高效的CD4T细胞反应的一个重要且未被描述的方面。我们的工作也 表明这种综合反应可以被优化，以改善病毒控制并减少 通过促进TRM与传统记忆CD4细胞中不同功能的免疫病理学。这 该提案将为疫苗如何最大限度地发挥本地和 系统的CD4记忆细胞，以提高疫苗诱导的对IAV的保护。 我们将优化模型以重建具有良好特征的肺TRM的不同种群的幼小鼠 和/或IAV激活的常规记忆CD4细胞。这一实验系统将有助于清楚地分析 TRM反应如何影响系统记忆CD4的再激活和后续反应参数 细胞感染IAV。我们的模型还将允许调整数字和功能容量 每个记忆隔间内的细胞，以便识别保护的独特子集特定关联。 我们还将在IAV免疫的小鼠中特异性地耗尽CD4TRM，从而允许进一步表征局部和 完整的免疫小鼠异亚型感染期间的系统记忆CD4协同作用。 在目标1中，我们将检验这样一种假设，即在IAV感染的最初几天内，肺内CD4TRM激活 提高次级淋巴器官的抗原呈递效率，导致更快地回忆起 常规记忆的CD4细胞。我们还将确定TRM是否会降低传统内存的大小 通过早期对病毒滴度和肺部炎症的控制而产生反应。在目标2中，我们将确定 整合记忆的CD4反应如何影响IAV清除和附带损伤的关键参数 而不是只用任一记忆子集重建的小鼠。最后，我们将确定协同作用的CD4是否 对IAV的保护可以通过限制原型T-bet依赖的Th1编程仅限于 TRM子集。这项工作将提供一个机制框架，以提高对CD4T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.