IRF4-Mediated Regulation of Lung Dendritic Cells During Viral Infection

描述（由申请人提供）：一种很有前途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并引发所需的T细胞反应。这种疫苗接种对流感病毒等呼吸道感染尤其有希望，因为鼻腔和肺组织中的常住dc对于感染或疫苗接种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存在于鼻组织和肺中的特定DC亚群的发育和功能反应是如何被调节的。在DC祖细胞中表达的特定转录因子控制着每个DC亚群在稳态期间的发育，但这些转录因子如何在病毒感染期间调节DC的新生发育和成熟功能尚不清楚。我们的目的是确定转录因子干扰素调节因子4 （IRF4）如何调节流感病毒感染期间肺DC亚群的新生发育和功能反应。为了进一步阐明IRF4的作用，我们开发了CD11c-cre-Irf4fl小鼠，在CD11c+前cdc和成熟dc中特异性地删除了0、1或2个条件Irf4fl等位基因拷贝。我们对这种新模型的初步研究表明，IRF4是肺驻留CD11b+ DC亚群发展所必需的。在流感病毒感染后，这种肺DC亚群的缺失导致肺DC细胞因子谱的改变，产生ifn γ的流感特异性CD8+ T细胞数量减少，感染的严重程度增加。基于这些数据，我们提出了IRF4的定量差异调节小鼠流感病毒感染期间肺CD11b+ dc的新生分化和形成成熟肺dc的功能反应的中心假设。为了验证这一假设并确定调节DC发育和功能的机制，我们将使用我们的新小鼠模型来解剖cdc前和DC限制性IRF4缺陷和单倍不足对DC介导的体内反应的影响。这一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DC亚群靶向人肺部疫苗接种战略。

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.