The role of cell death induced in microbial infections for the development of the antimicrobial immune response

这个项目的目的是了解在微生物感染过程中发生的细胞死亡对产生高效免疫反应的作用。如前所述，摄入细菌会导致粒细胞和巨噬细胞的细胞死亡。细胞死亡可以通过凋亡或坏死发生，并导致树突状细胞(DC)有效地摄取死亡细胞，树突状细胞将死亡细胞中包含的抗原递送给T细胞。进一步表明，病毒感染可导致感染细胞的坏死，而坏死再次足以使DC摄取死亡细胞。根据这些观察，我们得出假设，在微生物感染过程中诱导的细胞死亡是使微生物抗原可供DC和T细胞连续使用的重要途径。对这一概念的研究是这一提议的主题，并将包括以下问题的探索：1.决定死亡细胞摄取时产生免疫反应的因素是什么？2.细胞死亡的形式(细胞死亡或坏死，有或没有微生物的参与)和微生物依赖的刺激如何影响DC的成熟及其交叉呈递的能力？3.这些因素在体内如何影响适应性免疫反应的结果？这些问题将在转基因小鼠和受体非依赖性巨噬细胞刺激的模型中得到解决。实验系统将包括体外和体内DC和T细胞功能的研究。

The aim of this project is to understand the role of cell death that occurs during microbial infections for the development of a productive immune response. As we have shown earlier, ingestion of bacteria induces cell death in granulocytes and macrophages. Cell death can occur by either apoptosis or necrosis and leads to the efficient uptake of the dead cell by dendritic cells (DC), which in turn can present antigen contained in the dead cells to T cells. Viral infection was further shown to induce necrosis in infected cells, and necrosis was again sufficient for uptake of the dead cell by DC. From these observations we derive the hypothesis that cell death induced during microbial infections is an important way to make microbial antigen available to DC and consecutively to T cells. The investigation of this notion is the subject of this proposal, and will include exploration of the following questions: 1. What are the factors that determine the development of a productive immune response upon uptake of a dead cell? 2. How does the form of cell death (apoptosis or necrosis, with or without the participation of microbial agents) and microbe-dependent stimulation affect maturation of DC and their capacity for cross-presentation? 3. How do these factors contribute in vivo to determine the outcome of an adaptive immune response? These questions will be addressed in models of genetically modified mice and receptor-independent macrophage stimulation. Experimental systems will include in vitro and in vivo investigation of DC and T cell function.