Regulation of dendritic cells and their progenitors in infectious diseases

在对抗入侵病原体的机制和事件，如动员到感染部位或细胞凋亡导致免疫细胞的消耗。树突状细胞（DC）是适应性免疫反应的关键参与者，也是抗感染免疫的重要组成部分。因此，DC及其祖细胞在感染/炎症时的调节是一个新兴的感兴趣领域。在实验小鼠感染模型中使用模型病原体小肠结肠炎耶尔森氏菌（Ye），我们发现Ye感染导致脾DC数量的显著减少。这种作用依赖于TLR 4和TRIF信号，以及Ye-induced DC更新加快和抑制从头DC生成的净结果。然而，这背后的机制仍然难以捉摸。我们推测Ye可能通过微生物和/或炎症信号（如TLR配体、致病因子和干扰素）影响造血干细胞和祖细胞（HSPCs）和DC受体，从而影响机体对病原体的免疫力。因此，HSPCs及其后代的调控，重点是DC祖细胞将被分析后，感染不同的细菌病原体，以阐明可能的一般调控机制。具体来说，我们将重点分析微生物（TLR信号，直接和间接的影响）和炎症（干扰素，趋化因子和生长因子）信号的生存/增殖，迁移和分化的HSPCs和DC前体的基本影响。关于这一点的知识不仅可以为基础DC生物学提供新的见解，而且还可以确定感染性疾病中新的治疗靶点/诊断标志物。

Upon the fight against invading pathogens mechanisms and events such as mobilization to the sites of infection or apoptosis lead to the consumption of immune cells. Dendritic cells (DCs) are key players of the adaptive immune response and important components in immunity against infections. Therefore, the regulation of DCs and their progenitors upon infection/inflammation is an emerging field of interest. Using the model pathogen Yersinia enterocolitica (Ye) in an experimental mouse infection model we found that Ye infection causes a pronounced reduction of the number of splenic DCs. This effect was dependent on TLR4 and TRIF signaling, and the net result of Ye-induced faster DC turnover and sup-pression of de novo DC generation. However, the mechanism underlying this remains elusive. We hypothesize that Ye may affect hematopoietic stem and progenitor cells (HSPCs) and DC precur-sors by microbial and/or inflammatory signals, such as TLR ligands, pathogenicity factors and interferons and that this might influence immunity against the pathogen. Therefore, the regulation of HSPCs and their progeny with focus on DC progenitors will be analyzed upon infection with different bacterial pathogens to elucidate possible general regulation mechanisms. Specifically we will focus on analyzing the basic influence of microbial (TLR signaling, direct and indirect effects) and inflammatory (interferons, chemokines and growth factors) signals on survival/proliferation, migration and differentiation of HSPCs and DC precursors. Knowledge about this will not only give new insights into basic DC biology, but may also identify new therapeutic targets/diagnostic markers in infectious diseases.