T cell signal transduction in the regulation of T cell memory in response to infection

T 细胞信号转导在调节 T 细胞记忆响应感染中的作用

• 批准号: 10393762
• 负责人: Emma Teixeiro
• 金额: $ 26万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393762
• 关键词: Affect; Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cues; Data; Exposure to; Generations; Genetic Transcription; Health; Heterogeneity; Human; Immunity; Immunology; Infection; Influenza; Influenza vaccination; Knowledge; Laboratories; Ligands; Longevity; Lung; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Memory; Metabolism; Modeling; NF-kappa B; Pathogenicity; Phase; Population; Process; Property; Role; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Surveys; T cell regulation; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; TimeLine; Tissues; Vaccination; Vaccine Design; Vaccines; Work; adaptive immunity; base; design; fight against; gain of function; genetic manipulation; improved; influenza infection; influenza virus strain; loss of function; mouse model; novel; pathogen; programs; response

PROJECT SUMMARY Memory T cells rapidly and efficiently respond upon re-encountering pathogens, thanks to the existence of a diverse set of memory T cells with different migratory properties and functional capabilities. Memory CD8+ T cells can be broadly divided into 3 subsets: 2 highly mobile circulating memory CD8+ T cell subsets, termed central and effector memory T cells and a memory T cell pool that is resident in non- lymphoid tissues. The mechanisms that regulate this heterogeneity in the memory pool and whether these subsets are interdependent, or the generation of a specific memory population can be manipulated to the advantage of the host remain unknown in the field. Our preliminary data supports that the latter is possible and provides evidence for a critical role of NFkB signaling regulating T cell subset memory diversity. We will use novel inducible mouse models able to regulate the strength of NFkB signaling to mechanistically define how NFkB signals regulate resident and central memory generation and maintenance in the context of influenza infection (Aim 1). In Aim 2, we will employ different loss and gain of function models to determine how Pim1K, a novel downstream intermediate of NFkB signals in T cells, regulates T cell memory subset diversity. We anticipate that the information resulting from the studies proposed here will be highly significant. Data from these studies will advance the field of T cell memory where it is still unclear how each of the T cell memory subsets is regulated. Additionally, we expect that our results will provide with novel and critical avenues that will permit us to tune the generation of resident memory T cells in barrier tissues for the advantage of the host. This may be especially relevant for influenza infection and vaccination where TRM longevity is specially limited and critical for heterosubtypic immunity to IAV.

项目摘要 记忆T细胞在再次遇到病原体时迅速有效地做出反应，这要归功于一种免疫调节剂的存在。 不同的记忆T细胞具有不同的迁移特性和功能能力。记忆性CD8+ T细胞 可大致分为3个亚群：2个高度移动的循环记忆性CD8+ T细胞亚群，称为中央型 以及效应记忆T细胞和驻留在非淋巴组织中的记忆T细胞库。的机制 以及这些子集是相互依赖的，还是 可以操纵特定存储器群体的生成，以使主机保持未知， 外地我们的初步数据支持后者是可能的，并提供了证据，为关键作用， NFkB信号转导调节T细胞亚群记忆多样性。我们将使用新的可诱导小鼠模型， 调节NFkB信号传导的强度，以机械地定义NFkB信号如何调节驻留和中央 流感感染背景下的记忆产生和维持（目的1）。在目标2中，我们将采用 不同的功能模型的损失和增益，以确定如何Pim1K，一种新的下游中间NFkB 信号，调节T细胞记忆亚群多样性。我们预计， 这里提出的研究将是非常有意义的。这些研究的数据将推动T细胞记忆领域的发展 其中仍然不清楚T细胞记忆亚群中的每一个是如何被调节的。此外，我们希望我们的 结果将提供新的和关键的途径，这将使我们能够调整常驻记忆的产生 T细胞在屏障组织中对宿主有利。这可能与流感感染特别相关， 其中TRM寿命特别有限并且对于IAV的异亚型免疫至关重要的疫苗接种。