Wang J, Snider D P, Hewlett B R, Lukacs N W, Gauldie J, Liang H, Xing Z
Department of Pathology, Division of Infectious Diseases, Centre for Gene Therapeutics, McMaster University, Hamilton, ON, Canada.
Blood. 2000 Apr 1;95(7):2337-45.
The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the differentiation of dendritic cells (DCs) during pulmonary viral infection was investigated by using a mouse model of GM-CSF transgene expression established with an adenoviral vector (AdGM-CSF). GM-CSF gene transfer resulted in increased levels of GM-CSF in the lung, which peaked at day 4 and remained increased up to day 19. A striking cellular response composed predominantly of macrophage-like cells was observed in the lung receiving AdGM-CSF but not control vector. By FACS analysis, the majority of these cells were identified at an early time point as macrophages and later as mature/activated myeloid DCs characterized by CD11b(bright), CD11c(bright), MHC class II(bright), and B7.1(bright). In contrast, GM-CSF had a weak effect on a small DC population that was found present in normal lung and was characterized by CD11c(bright) and CD11b(low). By immunohistochemistry staining for MHC II, the majority of activated antigen-presenting cells were localized to the airway epithelium and peribronchial/perivascular areas in the lung. A concurrently enhanced Th1 immune response was observed under these conditions. The number of CD4 and CD8 T cells was markedly increased in the lung expressing GM-CSF, accompanied by increased release of interferon (IFN)gamma in the lung. Furthermore, lymphocytes isolated from either lung parenchyma or local draining lymph nodes of these mice but not the control mice released large amounts of IFNgamma on adenoviral antigen stimulation in vitro. These findings reveal that GM-CSF promotes the differentiation and activation of a myeloid DC population primarily by acting on macrophages during pulmonary immune responses.
通过使用腺病毒载体（AdGM-CSF）建立的GM-CSF转基因表达小鼠模型，研究了粒细胞-巨噬细胞集落刺激因子（GM-CSF）在肺部病毒感染期间树突状细胞（DC）分化中的作用。GM-CSF基因转移导致肺中GM-CSF水平升高，在第4天达到峰值，并持续升高至第19天。在接受AdGM-CSF而非对照载体的肺中观察到以巨噬细胞样细胞为主的显著细胞反应。通过流式细胞术分析，这些细胞中的大多数在早期被鉴定为巨噬细胞，后期被鉴定为成熟/活化的髓样DC，其特征为CD11b（明亮）、CD11c（明亮）、MHC II类（明亮）和B7.1（明亮）。相比之下，GM-CSF对正常肺中存在的一小部分以CD11c（明亮）和CD11b（低）为特征的DC群体作用较弱。通过MHC II免疫组织化学染色，大多数活化的抗原呈递细胞定位于肺中的气道上皮和支气管周围/血管周围区域。在这些条件下同时观察到Th1免疫反应增强。在表达GM-CSF的肺中，CD4和CD8 T细胞的数量显著增加，同时肺中干扰素（IFN）γ的释放也增加。此外，从这些小鼠而非对照小鼠的肺实质或局部引流淋巴结中分离的淋巴细胞在体外经腺病毒抗原刺激后释放大量IFNγ。这些发现表明，GM-CSF在肺部免疫反应期间主要通过作用于巨噬细胞来促进髓样DC群体的分化和活化。
