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CD4 T细胞是免疫力的关键编排。越来越清楚促进这种组织居民记忆（TRM）细胞的关键信号不会与支持传统记忆T细胞子集的支持生成。划定优化CD4 TRM生成的信号对于改善疫苗诱导的免疫力对诸如影响（IAV）等病原体的免疫力很重要仅抗体就无法提供持久的保护。我们的数据表明I型I干扰素（IFN）可以促进独特的激活模块，优化抗病毒CD4 T细胞效应到TRM的过渡，并且TH1 通过转录因子T-BET进行编程，限制了细胞采用此“ Pre-TRM”效应器的能力状态。该建议将分解I型IFN促进肺CD4能力的基础的关键机制 IAV感染期间的TRM和鼻内疫苗接种模型。在AIM 1中，我们将使用鼠标模型区分直接I型IFN信号与CD4 T细胞的方式，并间接通过调节炎症环境的影响，影响的功能和转录身份 TRM前效应，并最终塑造TRM景观。我们还将确定哪个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。在AIM 2中，我们将确定如何 IAV引发的CD4 T细胞通过信号换能器和转录激活剂解释I型IFN型信号（Stat）分子，以及I型IFN通过该类型的特定统计激活特征的程度当我们发现要确定内存命运时，动力学窗口。该分析将用于优化策略通过增加I型IFN响应CD4 T细胞的可用性来增强TRM。有效CD4的标志 TRM响应是它们的快速激活，导致系统性免疫反应之前控制病毒滴度开始。由于I型IFN对幼稚的CD4 T细胞激活产生抑制作用，我们提出CD4 TRM专业不仅可以在抗原相遇期间逃脱这种抑制作用，还可以避免使用I型 IFN作为急性“触发”，以优化他们的召回。在目标3中，我们将确定这种机制的程度运算符，以及TRM微调此响应的T-BET和特定stat表达方式。该提案将通过阐明如何利用I类IFN来提供高影响力的机械数据改善CD4 TRM的产生和回忆，与IAV以及可能的其他呼吸道病原体有关。我们的长期目标是制定疫苗和治疗策略，结合了这项研究的见解以改善肺中持久且快速响应的细胞免疫。