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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：
10650859
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/10650859
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 Interferons Kinetics Lead Lung Maintenance Mediating Memory Modeling Molecular Target Mus Outcome Pathogenicity Pathway interactions Phenotype Productivity Repression Research Role STAT protein STAT1 gene STAT4 gene Seasons Shapes Signal Transduction Site Structure of parenchyma of lung T cell response T memory cell T-Cell Activation T-Lymphocyte Subsets T-bet protein Testing Therapeutic Tissues Transcriptional Activation Vaccination Vaccines Viral Virus Virus Diseases conditioning cytokine directed differentiation effector T cell fitness functional outcomes global health improved improved outcome inflammatory milieu inflammatory modulation insight memory CD4 T lymphocyte memory recall mouse model neutralizing antibody pandemic disease pathogen programs respiratory pathogen respiratory virus response seasonal influenza tissue resident memory T cell 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.

项目摘要位于感染部位的记忆CD4T细胞是免疫的关键协调者。这一点越来越清楚促进这种组织驻留记忆(TRM)细胞的关键信号并不完全与那些支持生成常规存储器T细胞子集。描绘优化CD4TRM生成的信号对于提高疫苗诱导的对甲型流感病毒(IAV)等病原体的免疫力非常重要单靠抗体不能提供持久的保护。我们的数据表明，I型干扰素(干扰素)可以促进独特的激活模块，优化了抗病毒CD4T细胞效应器向TRM的转变，而Th1 通过转录因子T-bet进行编程，限制了细胞采用这种“前TRM”效应的能力州政府。这项提议将分解I型干扰素促进肺CD4能力的关键机制在IAV感染期间的TRM和鼻内接种的翻译模型中。在目标1中，我们将使用小鼠模型来区分如何将I型干扰素信号定向到CD4T细胞，以及如何间接通过调节炎症环境，影响细胞的功能和转录特性 TRM之前的效应器，并最终塑造TRM景观。我们还将确定T-投注的程度 CD4T细胞的表达影响I-干扰素调节TRM启动的能力。在目标2中，我们将确定如何 IAV免疫的CD4T细胞通过信号转导和转录激活因子解释I型干扰素信号 (STAT)分子，以及I型干扰素的特定STAT激活信号通过动力窗，当我们找到记忆的时候，命运就被决定了。这一分析将用于优化战略，以通过增加I型干扰素对应答的CD4T细胞的可获得性来促进TRM。有效的CD_4标志 TRM反应是它们的快速激活，导致在全身免疫反应之前控制病毒滴度都启动了。由于I型干扰素对初始的CD4T细胞活化有抑制作用，我们认为 TRM不仅专门用于在抗原相遇期间逃避这种抑制影响，而且还专门用于驾驭I型干扰素作为一种急性“触发器”，优化了他们的回忆。在目标3中，我们将确定该机制在多大程度上操作，以及T-bet和TRM的特定STAT表达式如何微调此响应。这项建议将通过阐明如何利用I型干扰素来提供高影响力的机制数据改善CD4TRM的产生和召回，与IAV和可能的其他呼吸道病原体相关。我们的长期目标是开发疫苗和治疗策略，结合这项研究的见解以改进肺中持久和快速反应的细胞免疫。