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IRF4-Mediated Regulation of Lung Dendritic Cells During Viral Infection

病毒感染期间 IRF4 介导的肺树突状细胞调节

基本信息

批准号：
8760146
负责人：
Susan Kovats
金额：
$ 43.62万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760146
关键词：
Affect Alleles Antigen Presentation Antigens B-Cell Development Body Weight decreased CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Cytokine Gene Data Dendritic Cells Dermal Development Dose Estrogens Generations Genes Homeostasis Human ITGAM gene ITGAX gene Immune response Immune system Infection Inflammatory Influenza Interferon Regulatory Factor 4 Interferons Knowledge Location Lung Lung Capacity Mediating Memory Modeling Morbidity - disease rate Mus Nose Outcome Pathology Pathway interactions Platelet Factor 4 Population Recovery Recruitment Activity Regulation Respiratory Tract Infections Role Severities Shapes Signal Pathway Stimulus Structure of parenchyma of lung T cell response T memory cell T-Lymphocyte Testing Trachea Vaccination Viral Virus Diseases Work base cytokine experience in vivo influenzavirus innovation interest lymph nodes migration monocyte mortality novel novel vaccines pandemic influenza pathogen progenitor programs public health relevance pulmonary vaccination respiratory response success transcription factor

项目摘要

DESCRIPTION (provided by applicant): A promising new vaccine strategy is to optimize antigen presentation and elicit desired T cell responses by targeting immunogens to specific dendritic cell (DC) subsets. Such vaccinations are especially promising for respiratory infections such as influenza virus, since resident DCs in nasal and lung tissue are crucial for initiation of beneficial immune responses after infection or vaccination. The success of this strategy requires understanding how the development and functional responses of specific DC subsets present in nasal tissue and lung are regulated. Specific transcription factors expressed in DC progenitors govern the development of each DC subset during homeostasis, but how these transcription factors regulate de novo DC development and mature DC function during viral infection is not known. Our objective here is to determine how the transcription factor interferon regulatory factor 4 (IRF4) regulates de novo development and functional responses of lung DC subsets during influenza virus infection. To further elucidate the role of IRF4, we have developed CD11c-cre-Irf4fl mice in which 0, 1 or 2 copies of a conditional Irf4fl allele are deleted specificlly in CD11c+ pre-cDCs and mature DCs. Our preliminary studies with this novel model suggest that IRF4 is required for the development of a lung resident CD11b+ DC subset. Upon influenza virus infection, the absence of this lung DC subset leads to an altered cytokine profile of lung DCs, reduced numbers of IFN?-producing influenza- specific CD8+ T cells and increased severity of infection. Based on these data, we propose the central hypothesis that quantitative differences in IRF4 regulate de novo differentiation of lung CD11b+ DCs and shape functional responses of mature lung DCs during influenza virus infection of mice. To test this hypothesis and define the mechanisms regulating DC development and function, we will use our new murine model to dissect the effects of pre-cDC- and DC-restricted IRF4 deficiency and haploinsufficiency on DC-mediated responses in vivo. The successful completion of this project is likely to provide new information that will support the development of DC subset-targeting strategies for human pulmonary vaccination against pandemic influenza viruses and other respiratory pathogens.

描述(由申请人提供)：一种有希望的新疫苗策略是通过将免疫原靶向特定的树突状细胞(DC)亚群来优化抗原呈递和诱导所需的T细胞反应。这种疫苗对于流感病毒等呼吸道感染特别有希望，因为鼻腔和肺组织中的常驻DC对于感染或接种疫苗后启动有益的免疫反应至关重要。这一策略的成功需要了解鼻组织和肺中存在的特定DC亚群的发育和功能反应是如何调节的。DC祖细胞表达的特定转录因子在动态平衡期间控制每个DC亚群的发育，但这些转录因子如何在病毒感染期间调节从头DC的发育和成熟的DC功能尚不清楚。我们的目标是确定转录因子干扰素调节因子4(IRF4)如何在流感病毒感染过程中调节肺DC亚群的新生发育和功能反应。为了进一步阐明IRF4的作用，我们建立了CD11c-cre-Irf4f1小鼠，在CD11c+前CDC和成熟DC中，条件Irf4f1等位基因的0、1或2个拷贝被特异性地缺失。我们对这一新模型的初步研究表明，IRF4是肺常驻CD11b+DC亚群发育所必需的。在流感病毒感染时，肺DC亚群的缺失会导致肺DC细胞因子谱改变，产生干扰素的流感特异性CD8+T细胞数量减少，感染严重程度增加。在这些数据的基础上，我们提出了一个中心假设，即IRF4的数量差异调节了肺CD11b+DC的从头分化，并塑造了成熟肺DC在流感病毒感染过程中的功能反应。为了验证这一假说并确定DC发育和功能的调控机制，我们将使用我们的新的小鼠模型来剖析CDC前和DC限制性的IRF4缺乏和单倍体不足对体内DC介导的反应的影响。该项目的成功完成可能会提供新的信息，支持制定针对大流行性流感病毒和其他呼吸道病原体的人类肺部疫苗DC亚群靶向战略。