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

优化局部和全身记忆 CD4 T 细胞对流感反应之间的功能协同作用

基本信息

批准号：
10317117
负责人：
Karl Kai McKinstry
金额：
$ 18.64万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-10 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317117
关键词：
Activities of Daily Living Adoptive Transfer Affect Antigen Presentation Antigens Antiviral Response CD4 Positive T Lymphocytes Cells Cellular Immunity Characteristics Combined Vaccines Data Emigrations Experimental Models Future Genetic Transcription Genotype Goals Heterogeneity Immune Immunity Infection Inflammation Inflammatory Influenza Influenza A virus Lung Mediating Memory Modeling Morbidity - disease rate Mus Outcome Pathway interactions Pattern Recognition Phase Population Production Route Secondary to Site Structure of parenchyma of lung System T cell response Testing Tissues Uncertainty Vaccinated Vaccination Vaccine Design Vaccines Viral Viral Physiology Virus Virus Diseases Work cell type combat design global health immunopathology improved improved outcome inflammatory milieu influenza infection influenza virus vaccine innovation insight memory CD4 T lymphocyte memory recall neutralizing antibody novel novel vaccines pathogen reconstitution response secondary lymphoid organ synergism vaccine-induced immunity

项目摘要

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.

摘要/摘要针对甲型流感病毒 (IAV) 的保护性记忆 CD4 T 细胞反应涉及多种细胞类型具有独特的特点。异质性的一个新兴轴是肺组织驻留之间的划分记忆细胞（TRM）和通过次级淋巴器官循环的传统记忆细胞。大多数研究迄今为止，我们的重点是在回忆期间单独表征这些子集的抗病毒活性回应。然而，我们的初步研究支持区域和系统之间协同作用的概念记忆细胞是高效 CD4 T 细胞反应的一个重要且未表征的方面。我们的工作也表明这种综合反应可以优化以改善病毒控制并减少通过促进 TRM 与传统记忆 CD4 细胞的不同功能来进行免疫病理学研究。这该提案将为疫苗如何最大限度地发挥地方和疫苗之间的协同作用提供新的机制见解。全身性 CD4 记忆细胞可改善疫苗诱导的 IAV 保护。我们将优化模型以重建具有良好特征的肺 TRM 的独立群体的初始小鼠和/或由 IAV 引发的常规记忆 CD4 细胞。该实验系统将有助于清晰地分析 TRM 反应如何影响系统记忆 CD4 的重新激活和后续反应参数 IAV 感染后的细胞。我们的模型还将允许调制数量和功能能力每个记忆隔室中的单元，以便识别独特的特定于子集的保护相关性。我们还将专门耗尽 IAV 免疫小鼠中的 CD4 TRM，从而进一步表征局部和完整接种疫苗的小鼠异亚型感染期间的系统记忆 CD4 协同作用。在目标 1 中，我们将检验以下假设：肺 CD4 TRM 在 IAV 感染的最初几天内激活提高次级淋巴器官中抗原呈递的效率，从而更快地回忆传统的记忆CD4细胞。我们还将确定 TRM 是否会减少传统内存的大小通过早期控制病毒滴度和肺部炎症来做出反应。在目标 2 中，我们将确定集成记忆 CD4 反应如何影响 IAV 清除和附带损害的关键参数与仅用任一记忆子集重建的小鼠相比。最后，我们将确定CD4是否具有协同作用通过将依赖于 T-bet 的原型 Th1 编程限制为仅 TRM 子集。这项工作将提供一个机制框架来改善 CD4 T 细胞依赖性保护 IAV 和其他病原体并优化创新实验系统以促进未来的发现。