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

基本信息

批准号：
10299358
负责人：
Weishan Huang
金额：
$ 38.24万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
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/10299358
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 In Vitro Individual Infection Inflammatory Inflammatory Response Influenza Influenza A virus Interferons Interleukin-10 Lead Learning Lung Lung diseases 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 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

项目摘要

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.

项目摘要/摘要流感（流感）感染是世界呼吸道疾病和相关死亡的主要原因。估计年度流感流行病会导致3-5万例严重疾病，超过250,000例死亡人数。需要强大的效应子免疫来进行病毒清除，但是，如果没有，它可能会导致免疫病理学正确控制。严重和致命的流感疾病伴随着侵略性的促炎反应和抗炎免疫不足。免疫调节细胞因子IL-的产生 10通过流感特异性CD8+ T细胞在限制感染过程中肺部免疫病理学至关重要，有助于宿主的生存和恢复。知道如何识别这些调节性CD8+ T细胞并了解它们如何发展和功能对于学习如何控制流感诱导的肺免疫病理学至关重要。这使得我们的工作非常重要。虽然对CD4+调节T细胞知之甚少，但分子特征以及调节IL-10+调节CD8+ T细胞的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背景下。我们最近产生了一个IL- 10GFP/FOXP3RFP双向报告鼠标模型，可在活细胞中检测IL-10和FOXP3，以及对正常和肺部下的IL-10+和/或Foxp3+ T细胞的存在进行了筛选炎症条件。我们发现foxp3-il-10+ cd8+ t细胞存在于各种器官和疾病中条件，是流感感染期间气道IL-10产量的主要因素。这些 FOXP3-IL-10+ CD8+ T细胞表现出针对促炎的先天性和适应性免疫反应，表明具有治疗潜力。但是，没有可靠的标记 FOXP3-IL-10+ CD8+调节T细胞。我们假设分子特征和相关的途径随着IL-10产生调节性CD8+ T细胞的发展和功能，可以利用制定针对流感诱导的肺免疫病理学的治疗策略。我们的初步研究确定了一种新型的表面签名lag3hicd25 hibtlalocd226lo和临界转录流感感染期间IL-10+ CD8+ T细胞中的TCF1因子TCF1。我们提出了两个具体目的的实验：（1）确定并验证IL-10产生调节性CD8+ T细胞的特征表面标记；（2）确定TCF1在IL-10产生的调节性CD8+ T细胞的开发和功能中的作用。这项工作是高度创新的，因为我们利用具有独特的全面生化，遗传和基因组学方法转基因鼠标模型，并具有令人兴奋的初步数据，可以扩展以提供信息表面标记和关键信号通路，以更好地理解开发和流感感染过程中产生IL-10的CD8+ T细胞的免疫调节功能。我们希望解散可以更好地控制流感诱导的发病机理的潜在分子机制，这可能增强我们制定控制病毒诱导的免疫病理学，发病率和死亡率的策略的能力。