Markers and regulation of regulatory CD8+ T cells during influenza-induced lung immunopathology

流感诱导的肺免疫病理过程中调节性 CD8 T 细胞的标志物和调控

• 批准号: 10437918
• 负责人: Weishan Huang
• 金额: $ 38.27万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437918
• 关键词: ATAC-seq; Acute; Adaptive Immune System; Adoptive Cell Transfers; Anti-Inflammatory Agents; Antigens; Binding; Binding Sites; Biochemical Genetics; Biological Markers; Biological Response Modifiers; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell model; Cells; Cessation of life; ChIP-seq; Coronavirus; DNA Binding; Data; Detection; Development; Disease; Event; Exhibits; Extrinsic allergic alveolitis; FOXP3 gene; Genetic Polymorphism; Genetic Transcription; Genomic approach; Human; IL10 gene; IL2RA gene; Immunity; Immunosuppression; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Interferons; Interleukin-10; Lead; Learning; Lung; Memory; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Organ; PTPRC gene; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Peripheral Blood Mononuclear Cell; Population; Production; Protocols documentation; Recovery; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Respiratory Disease; Risk; Role; Seasons; Signal Pathway; Signal Transduction; Surface; T cell differentiation; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Transcriptional Regulation; Transgenic Mice; Viral; Virus; Virus Diseases; Work; adaptive immune response; airway inflammation; congenic; cytokine; effector T cell; experimental study; flu; genetic approach; immunopathology; immunoregulation; in vivo; influenza epidemic; influenza infection; influenza virus strain; innovation; macrophage; mortality; mouse model; novel; pandemic disease; phenotypic biomarker; screening; transcription factor; transcriptome sequencing

Project Summary/Abstract Influenza (Flu) infection is a leading cause of respiratory disease and associated death in the world. The annual flu epidemics are estimated to result in 3-5 million cases of severe illness and more than 250,000 deaths. A strong effector immunity is desired for viral clearance, it however can lead to immunopathology if not properly controlled. Severe and fatal influenza diseases are accompanied by an aggressive pro-inflammatory response and an insufficient anti-inflammatory immunity. The production of the immunoregulatory cytokine IL- 10 by flu-specific CD8+ T cells is critical in limiting the lung immunopathology during infection, contributing to host survival and recovery. Knowing how to identify these regulatory CD8+ T cells and understanding how they develop and function are essential for learning how to control flu-induced lung immunopathology. This makes our work highly significant. While much is known about the CD4+ regulatory T cells, the molecular signature and mechanisms that regulate the development and function of IL-10+ regulatory CD8+ T cells remain poorly understood, particularly in the context of influenza-induced airway inflammation. We recently generated an IL- 10GFP/Foxp3RFP dual reporter mouse model that enables detection of IL-10 and Foxp3 in live cells, and undertook a screening for the presence of IL-10+ and/or Foxp3+ T cells under normal and pulmonary inflammatory conditions. We found that Foxp3- IL-10+ CD8+ T cells are present in various organs and disease conditions, and are the major contributors to IL-10 production in the airway during influenza infection. These Foxp3- IL-10+ CD8+ T cells exhibit profound immunoregulatory function against pro-inflammatory innate and adaptive immune responses, indicative of a therapeutic potential. There are however no reliable markers for Foxp3- IL-10+ CD8+ regulatory T cells. We hypothesize that molecular signatures and pathways associated with the development and function of IL-10-producing regulatory CD8+ T cells can be exploited to develop therapeutic strategies against influenza-induced lung immunopathology. Our preliminary studies identified a novel surface signature LAG3hiCD25hiBTLAloCD226lo and the critical transcription factor TCF1 in IL-10+ CD8+ T cells during influenza infection. We propose experiments in two Specific Aims to: (1) determine and validate signature surface markers of IL-10-producing regulatory CD8+ T cells; and (2) determine the role of TCF1 in IL-10-producing regulatory CD8+ T cell development and function. This work is highly innovative as we utilize comprehensive biochemical, genetic and genomics approaches with unique transgenic mouse models, and have exciting preliminary data that can be expanded to provide information of surface markers and critical signaling pathways for a better understanding of the development and immunoregulatory function of IL-10-producing CD8+ T cells during Influenza infection. We expect to unravel potential molecular mechanisms through which flu-induced pathogenesis can be better controlled, which may enhance our ability of developing strategies to control virus-induced immunopathology, morbidity and mortality.

项目概要/摘要 流感 (Flu) 感染是世界范围内呼吸系统疾病和相关死亡的主要原因。 每年流感流行预计会导致 3-500 万重症病例和超过 25 万例死亡 死亡人数。病毒清除需要强大的效应子免疫力，但如果不这样做，可能会导致免疫病理学 适当控制。严重和致命的流感疾病伴随着侵袭性的促炎症反应 反应和抗炎免疫力不足。免疫调节细胞因子 IL-的产生 10 流感特异性 CD8+ T 细胞对于限制感染期间的肺部免疫病理学至关重要，有助于 宿主的生存和恢复。了解如何识别这些调节性 CD8+ T 细胞并了解它们如何 发育和功能对于学习如何控制流感引起的肺部免疫病理学至关重要。这使得 我们的工作非常重要。虽然人们对 CD4+ 调节性 T 细胞了解很多，但其分子特征 调节 IL-10+ 调节性 CD8+ T 细胞发育和功能的机制仍然很差 理解，特别是在流感引起的气道炎症的情况下。我们最近生成了一个 IL- 10GFP/Foxp3RFP 双报告小鼠模型，能够检测活细胞中的 IL-10 和 Foxp3，以及 对正常和肺条件下 IL-10+ 和/或 Foxp3+ T 细胞的存在进行了筛查 炎症状况。我们发现Foxp3- IL-10+ CD8+ T细胞存在于多种器官和疾病中 是流感感染期间气道中 IL-10 产生的主要贡献者。这些 Foxp3- IL-10+ CD8+ T 细胞对促炎先天性和 适应性免疫反应，表明治疗潜力。但目前还没有可靠的标记 Foxp3- IL-10+ CD8+ 调节性 T 细胞。我们假设分子特征和相关途径 随着产生 IL-10 的调节性 CD8+ T 细胞的发育和功能，可用于 制定针对流感引起的肺部免疫病理学的治疗策略。我们的初步 研究发现了一种新的表面特征 LAG3hiCD25hiBTLAloCD226lo 和关键转录 流感感染期间 IL-10+ CD8+ T 细胞中的 TCF1 因子。我们提出两个具体目标的实验： (1) 确定并验证产生 IL-10 的调节性 CD8+ T 细胞的特征表面标记；和（2） 确定 TCF1 在产生 IL-10 的调节性 CD8+ T 细胞发育和功能中的作用。这部作品是 高度创新，因为我们利用综合生化、遗传学和基因组学方法，具有独特的 转基因小鼠模型，并拥有令人兴奋的初步数据，可以扩展以提供以下信息： 表面标记和关键信号通路，以便更好地了解发育和 流感感染期间产生 IL-10 的 CD8+ T 细胞的免疫调节功能。我们期待解开 可以更好地控制流感诱发的发病机制的潜在分子机制，这可能 增强我们制定控制病毒引起的免疫病理学、发病率和死亡率的策略的能力。