Harnessing type I interferon to promote lung-resident memory CD4 T cell immunity against influenza

利用I型干扰素促进肺驻留记忆CD4 T细胞对流感的免疫

• 批准号: 10417904
• 负责人: Karl Kai McKinstry
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417904
• 关键词: Acute; Address; Adopted; Animal Model; Antibodies; Antigens; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Clinical Research; Data; Disease Outcome; Dominant-Negative Mutation; Effectiveness; Elements; Environment; Epitopes; Gene Expression; Generations; Genetic Transcription; Goals; Immune; Immune response; Immunity; Infection; Inflammatory; Influenza; Influenza A virus; Interferon Type I; Interferon-alpha; Interferons; Kinetics; Lead; Lung; Maintenance; Mediating; Memory; Modeling; Molecular Target; Mus; Outcome; Pathogenicity; Pathway interactions; Phenotype; Research; Role; STAT protein; STAT1 gene; STAT4 gene; Shapes; Signal Transduction; Site; Structure of parenchyma of lung; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; T-bet protein; Testing; Therapeutic; Tissues; Transcriptional Activation; Vaccination; Vaccines; Viral; Virus; Virus Diseases; base; conditioning; cytokine; directed differentiation; effector T cell; fitness; functional outcomes; global health; improved; improved outcome; inflammatory milieu; insight; memory CD4 T lymphocyte; memory recall; mouse model; neutralizing antibody; pandemic disease; pathogen; programs; respiratory pathogen; respiratory virus; response; seasonal influenza; translational model; treatment optimization; universal influenza vaccine; vaccination strategy; vaccine development; vaccine efficacy; vaccine-induced immunity

Project Summary Memory CD4 T cells residing at sites of infection are key orchestrators of immunity. It is increasingly clear that key signals promoting such tissue-resident memory (TRM) cells do not overlap completely with those that support generation of conventional memory T cell subsets. Delineating signals that optimize CD4 TRM generation is important to improve vaccine-induced immunity against pathogens like influenza A virus (IAV) against which antibody alone cannot confer lasting protection. Our data indicates that type I interferons (IFN) can promote a unique activation module that optimizes the transition of anti-viral CD4 T cell effectors into TRM, and that Th1 programming, through the transcription factor T-bet, restricts the ability of cells to adopt this ‘pre-TRM’ effector state. This proposal will breakdown key mechanisms underlying the ability of type I IFN to promote lung CD4 TRM during IAV infection and in a translational model of intranasal vaccination. In Aim 1, we will use mouse models to differentiate how direct type I IFN signals to CD4 T cells, and indirect effects through modulating the inflammatory environment, impact the functional and transcriptional identity of pre-TRM effectors and ultimately shape the TRM landscape. We will also determine the extent to which T-bet expression by CD4 T cells effects the ability of I IFN to modulate TRM priming. In Aim 2, we will determine how IAV-primed CD4 T cells interpret type I IFN signals through signal transducer and activator of transcription (STAT) molecules, and the extent to which specific STAT activation signatures by type I IFN change through the kinetic window when we find memory fate to be determined. This analysis will be used to optimize strategies to boost TRM through increasing availability of type I IFN to responding CD4 T cells. A hallmark of effective CD4 TRM responses is their rapid activation which results in control of viral titers before systemic immune responses are initiated. As Type I IFNs have a suppressive impact on naive CD4 T cell activation, we propose that CD4 TRM are specialized to not only escape this suppressive impact during antigen encounter, but to harness type I IFN as an acute ‘trigger’ optimizing their recall. In Aim 3 we will determine the extent to which this mechanism operates, and how T-bet and specific STAT expression by TRM fine-tune this response. This proposal will provide high impact mechanistic data by elucidating how type I IFN can be harnessed to improve the generation and recall of CD4 TRM, with relevance to IAV and likely other respiratory pathogens. Our long-term goal is develop vaccine and therapeutic strategies incorporating insights from this research to improve durable and rapidly responsive cellular immunity in the lung.

项目概要 存在于感染部位的记忆 CD4 T 细胞是免疫的关键协调者。已经越来越清晰 促进这种组织驻留记忆（TRM）细胞的关键信号与那些促进组织驻留记忆（TRM）细胞的关键信号并不完全重叠 支持传统记忆 T 细胞子集的生成。描绘优化 CD4 TRM 生成的信号 对于提高疫苗诱导的针对甲型流感病毒 (IAV) 等病原体的免疫力非常重要 单独的抗体不能提供持久的保护。我们的数据表明，I 型干扰素 (IFN) 可以促进 独特的激活模块，优化抗病毒 CD4 T 细胞效应器向 TRM 的转变，并且 Th1 通过转录因子 T-bet 进行编程，限制细胞采用这种“TRM 前”效应器的能力 状态。该提案将分解 I 型 IFN 促进肺 CD4 能力的关键机制 IAV 感染期间和鼻内疫苗接种转化模型中的 TRM。 在目标 1 中，我们将使用小鼠模型来区分 I 型 IFN 如何直接向 CD4 T 细胞发出信号，以及如何间接向 CD4 T 细胞发出信号。 通过调节炎症环境，影响功能和转录特性 TRM 前效应器并最终塑造 TRM 景观。我们还将确定 T 下注的程度 CD4 T 细胞的表达会影响 I IFN 调节 TRM 启动的能力。在目标 2 中，我们将确定如何 IAV 引发的 CD4 T 细胞通过信号转导器和转录激活剂解​​释 I 型 IFN 信号 (STAT) 分子，以及 I 型 IFN 改变的特定 STAT 激活特征的程度 当我们发现记忆命运待决定时的动力学窗口。该分析将用于优化策略 通过增加 I 型 IFN 对响应 CD4 T 细胞的可用性来增强 TRM。有效 CD4 的标志 TRM 反应是它们的快速激活，导致在系统免疫反应之前控制病毒滴度 被发起。由于 I 型 IFN 对初始 CD4 T 细胞活化具有抑制作用，因此我们建议 CD4 TRM 专门用于逃避抗原遇到过程中的这种抑制影响，还可以利用 I 型抗原 干扰素作为一种急性“触发因素”，可以优化他们的回忆。在目标 3 中，我们将确定该机制的程度 运作，以及 T-bet 和 TRM 的特定 STAT 表达如何微调这种反应。 该提案将通过阐明如何利用 I 型干扰素来提供具有高影响力的机制数据。 改善与 IAV 和可能的其他呼吸道病原体相关的 CD4 TRM 的生成和召回。我们的 长期目标是结合本研究的见解来开发疫苗和治疗策略，以改善 肺部持久且快速反应的细胞免疫。