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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要人们越来越清楚，存在于感染部位的记忆 CD4 T 细胞是免疫的关键协调者。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) 可以促进保护。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”效应子的能力该提案将分解 I 型 IFN 促进肺部 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来发挥作用 TRM 之前的效应器并最终塑造 TRM 格局，我们还将确定 T-bet 的程度。 CD4 T 细胞的表达会影响 I IFN 调节 TRM 启动的能力。 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定时，动力学窗口将用于优化策略。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，我们将确定这种机制的程度。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 和其他可能的呼吸道病原体相关的 CD4 TRM 的生成和召回。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。