Impact of bacterial infection on myeloid dendritic cell development

描述(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具有巨大的潜力。由于其强大的刺激T细胞反应的能力，树突状细胞作为各种疾病的疫苗正受到密切的研究，并在癌症领域显示出特别的前景。树突状细胞是一组不同的细胞，具有不同的表型和功能，代表其独特的亚群和谱系。多年来，GM-CSF已被成功地用于体外研究中大量产生DC，并且仍然是用于疫苗产生DC的主要细胞因子。通过GM-CSF活性发展和分化的DC被认为代表了一种独特的髓系血统，DC的直接前体是单核细胞。当感染包括单核细胞增多性李斯特菌在内的各种病原体时，感染动物的血清中可观察到GM-CSF的激增。然而，髓系祖细胞类型在感染性疾病过程中的作用仍未完全明确。因此，通过这一提议，我们将检验这样一个假设，即感染发育不良的髓系细胞(普通髓系祖细胞和单核/树突状细胞祖细胞)感染李斯特氏菌将通过赋予免疫抑制功能和促进细菌的生长和传播来抑制整体免疫反应。为了验证这一假设，我们提出了两个具体的目标：1)确定不同发育阶段的髓系细胞感染如何影响其作为抗原提呈细胞的功能。 2)确定髓系细胞的发育状态如何影响李斯特菌在细胞内的命运。

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.