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：
8916820
负责人：
Susan Kovats
金额：
$ 42.66万
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/8916820
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 Health Homeostasis Human ITGAM gene ITGAX gene Immune response Immune system Infection Inflammatory Influenza Interferon Regulatory Factor 4 Interferon Type II 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 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 IFNγ-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（由适用提供）：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）亚群来优化抗原表现，并引起所需的T细胞反应。对于呼吸道感染（例如影响）病毒，这种疫苗尤其有希望，因为鼻和肺组织中的居民DC对于感染或疫苗后有益免疫反应的倡议至关重要。该策略的成功需要了解鼻组织和肺中存在的特定DC子集的发展和功能响应如何受到调节。 DC祖细胞中表达的特定转录因子控制着体内稳态过程中每个DC子集的发展，但是这些转录因子如何调节从头DC的发展和病毒感染期间成熟的DC功能。我们的目的是确定转录因子干扰素调节因子4（IRF4）如何调节在影响力病毒感染期间肺直流亚群的从头发展和功能反应。为了进一步阐明IRF4的作用，我们开发了CD11C-CRE-IRF4FL小鼠，其中有条件IRF4FL等位基因的0、1或2副本专门在CD11C+ PERCDC和成熟的DC中删除。我们使用这种新型模型的初步研究表明，开发肺CD11b+ DC子集需要IRF4。该肺直流体系的影响会导致肺DC的细胞因子谱改变，减少了IFNγ产生的影响构成的造成影响，特异性CD8+ T细胞并增加了感染的严重程度。基于这些数据，我们提出了一个中心假设，即IRF4的定量差异调节肺CD11b+ DC的从头分化以及在小鼠感染中成熟的肺DC的形状功能反应。为了检验这一假设并定义了DC开发和功能的机制，我们将使用新的鼠模型来剖析CDC和DC限制的IRF4缺乏症和单倍弥补对体内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，以支持针对大流行的人类肺疫苗的DC子集靶向策略的发展，以影响病毒和其他呼吸道病原体。