Impact of bacterial infection on myeloid dendritic cell development

描述（由申请人提供）：树突状细胞在需要调节免疫反应的临床应用中提供了巨大的潜力。由于其刺激 T 细胞反应的强大能力，DC 作为多种疾病的疫苗正在接受深入研究，并在癌症领域显示出特别的前景。 DC 是一组具有不同表型的多样化细胞，其功能代表其独特的子集和谱系。 GM-CSF 多年来已成功用于产生大量 DC 用于体外研究，并且仍然是用于产生疫苗 DC 的主要细胞因子。通过 GM-CSF 活性发育和分化的 DC 被认为代表了独特的骨髓谱系，并且 DC 的直接前体是单核细胞。在感染包括单核细胞增生李斯特氏菌在内的多种病原体后，在受感染动物的血清中观察到 GM-CSF 激增。然而，骨髓祖细胞类型在传染病过程中的功能仍未完全确定。因此，通过这项提议，我们将检验以下假设：用李斯特菌感染发育不良的骨髓细胞（共同骨髓祖细胞和单核细胞/树突细胞祖细胞）将通过赋予免疫抑制功能并增强细菌的生长和传播来抑制整体免疫反应。为了检验这一假设，我们提出了两个具体目标：1）确定不同发育阶段的骨髓细胞感染如何影响其作为抗原呈递细胞的功能。 2) 确定骨髓细胞的发育状态如何影响细胞内李斯特菌的命运。

DESCRIPTION (provided by applicant): Dendritic cells offer tremendous potential in clinical applications where modulating immune responses are desired. Thanks to their potent ability to stimulate T cell responses, DC are under intense investigation as vaccines for a variety of diseases, and have shown particular promise in the cancer arena. DC are a diverse group of cells with distinct phenotypes, and functions representative of their unique subset and lineage. GM-CSF has been used successfully for years to generate large numbers of DC for study in vitro and is still the predominant cytokine used to generated DC for vaccines. DC that are developed and differentiated through GM-CSF activity are thought to represent a distinct myeloid lineage and the immediate precursors of DCs are monocytes. Upon infection with a variety of pathogens including Listeria monocytogenes, a surge in GM-CSF is observed in the serum of infected animals. However, the function of myeloid progenitor cell types in the infectious disease process remains incompletely defined. Therefore with this proposal we will test the hypothesis that infection of poorly developed myeloid cells (common myeloid progenitors and monocyte/dendritic cell progenitors) with Listeria will inhibit the overall immune response by imparting immunosuppressive function and enhancing the growth and spread of bacteria. To test this hypothesis we propose two specific aims: 1) To determine how infection of myeloid cells at distinct stages of development affects their function as antigen presenting cells. And 2) To determine how the developmental status of myeloid cells affects the fate of Listeria within the cell.