Control of CD4 T cell effector function and tissue-resident memory fate by the transcription factor Eomes

转录因子 Eomes 控制 CD4 T 细胞效应功能和组织驻留记忆命运

• 批准号: 9807682
• 负责人: Karl Kai McKinstry
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-13 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807682
• 关键词: Activities of Daily Living; Animal Model; Attenuated; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Data; Effector Cell; Elements; Ensure; Environment; Epitopes; Event; Gene Expression; Gene Proteins; Generations; Genetic Transcription; Heterogeneity; Humoral Immunities; Immune; Immunity; Immunization; Infection; Influenza; Influenza A virus; Influenza vaccination; Link; Location; Lung; Memory; Meta-Analysis; Modeling; Mus; Pathway interactions; Pattern; Peptides; Phenotype; Population; Production; Regulation; Role; Signal Transduction; Site; Structure of parenchyma of lung; System; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tissues; Transcriptional Regulation; Transgenic Organisms; Vaccination; Vaccine Design; Vaccines; Viral; Virulent; Virus; Virus Diseases; base; combat; cost; cytokine; cytotoxic; cytotoxicity; effector T cell; genetic signature; human disease; improved; influenzavirus; innovation; insight; memory CD4 T lymphocyte; mouse model; novel; overexpression; pathogen; respiratory; response; transcription factor

Abstract Specialized tissue-resident memory (TRM) T cells that persist at sites of infection are emerging as critical constituents of protective immunity. Designing vaccines that target the induction of lung TRM is a promising approach to improve protection against influenza, especially as T cells recognize peptide epitopes expressed across diverse viral strains, providing an avenue towards ‘universal’ protection. However, the transcriptional regulation controlling the transition of effector CD4 T cells to TRM is poorly understood, nor is it clear whether or not particular subsets of effector cells have a greater capacity to form TRM. This proposal will provide novel insight into the correlates of protective CD4 T cell responses against influenza, and produce high impact mechanistic data required to better elucidate the regulation of lung TRM generation. We recently developed an innovative murine influenza model in which the memory fate of virus-specific CD4 T cells can be restricted to only form highly functional and protective lung TRM. Our preliminary studies find dramatically increased expression of the transcription factor Eomesodermin (Eomes) in effectors that can only act as precursors for TRM versus in cells that can form circulating memory subsets. The role of Eomes during pathogen-specific CD4 T cell responses is not well-defined, but has been found to regulate aspects of cytokine production and cytotoxic programming in other animal models and human disease states. Through meta- analysis, we find unexpected overlap in gene signatures of cytolytic CD4 T cells and CD4 TRM, and that effectors with higher Eomes levels have increased cytotoxic capacity. We thus hypothesize that Eomes promotes a unique effector state in CD4 T cell effectors that is required to generate lung TRM and that is marked by a specialized functional repertoire including cytotoxicity. By modulating Eomes expression in CD4 T cells responding to influenza infection and intranasal vaccination, this proposal will provide clear and novel findings needed for innovative strategies to promote the most protective kinds of CD4 memory in the right locations. In Aim 1, we will determine the extent to which Eomes regulates cytokine production and cytotoxic potential in CD4 effectors, as well as how Eomes impacts transcriptional regulation during the effector to memory transition. We will also directly test the protective capacity of Eomes-deficient versus wild-type CD4 effectors. In Aim 2, we will determine how Eomes impacts the lung CD4 TRM landscape, and the extent to which hallmark protective TRM functions are modulated in Eomes-deficient cells. Finally, we will whether high Eomes expression in effector cells acts as a rheostat to limit their ability to give rise to circulating memory cells.

抽象的 在感染部位持续存在的专业组织居民记忆（TRM）T细胞正在成为关键 受保护免疫的成分。设计靶向肺TRM诱导的疫苗是一种承诺 改善影响影响的方法，尤其是当T细胞识别表达的肽表位 跨越潜水的病毒菌株，为“普遍”保护提供了途径。但是，转录 控制效应CD4 T细胞向TRM的过渡的调节尚不清楚，也不清楚是否清楚或 效应细胞的特定子集具有更大的形成TRM的能力。该建议将提供小说 深入了解受保护的CD4 T细胞反应针对影响力的相关性，并产生高影响 更好地阐明肺TRM生成调节所需的机械数据。 我们最近开发了一种创新的鼠影响模型，其中病毒特异性的记忆命运 CD4 T细胞可以仅限于形成高度功能和受保护的肺TRM。我们的初步研究发现 转录因子Eomesodermin（EOMES）的表达大大增加了，只能 在可以形成循环记忆子集的细胞中，充当TRM与TRM的前体。 EOMES在 病原体特异性的CD4 T细胞反应不是明确的，但已被发现调节细胞因子方面 在其他动物模型和人类疾病状态下的生产和细胞毒性编程。通过meta- 分析，我们发现细胞溶解CD4 T细胞和CD4 TRM的基因特征的意外重叠，这会影响 较高的EOMES水平具有增加的细胞毒性能力。因此，我们假设Eomes促进了 CD4 T细胞效应中的独特效应态，这是生成肺TRM所需的，并且标记为 包括细胞毒性的专门功能曲目。通过调节CD4 T细胞中的Eomes表达 该提案应对影响扎感染和鼻内疫苗接种，将提供清晰而新颖的发现 创新策略需要在正确的位置促进最受保护的CD4存储器类型。 在AIM 1中，我们将确定Eomes调节细胞因子产生和细胞毒性的程度 CD4效应的潜力以及EOMES如何影响效应器期间的转录调节到记忆 过渡。我们还将直接测试EOMES缺陷与野生型CD4效应的保护能力。 在AIM 2中，我们将确定Eomes如何影响肺CD4 TRM景观以及标志的程度 保护性TRM功能在EOMES缺陷细胞中进行了调节。最后，我们将是否表达高EOMES 在效应细胞中充当阻尼斯特，以限制其产生循环记忆细胞的能力。