Role of CD8+ dendritic cells in antigen (cross-) presentation and cytotoxic immunity of the mouse and the human

在免疫系统中，抗原被“树突状细胞”(DC)摄取和处理，其中一个重要的亚群(20%)是CD8+DC。由于缺乏合适的实验系统，CD8+DC对抗原(交叉)提呈的确切贡献至今无法评估，这是建立免疫耐受和产生免疫的绝对核心过程。然而，大量数据表明，这些CD8+DC在对病毒、细胞内细菌和某些肿瘤的细胞毒反应的发展中起着关键作用。基于对CD8+树突状细胞表面受体的鉴定，我们将能够在小鼠中从基因上删除这些树突状细胞，从而确定它们在稳态(耐受)和感染(免疫)中的作用。这些研究将伴随着许多旨在确定CD8+DC在野生型小鼠不同器官中的功能的方法。同时，我们将鉴定小鼠CD8+DC的人类对应物。这些人类DC将进行表型鉴定和功能测试，特别是它们将抗原(交叉)呈递给CD8+T细胞的能力，CD8+T细胞是细胞毒免疫防御的支柱。这些基础研究将提供信息，使我们能够在未来开发根本上优化的新型疫苗，以诱导针对病毒疾病和肿瘤的细胞毒性T细胞。

In the immune system, antigen is taken up and processed by “dendritic cells” (DC), of which an important subgroup (20%) are CD8+DC. The exact contribution of CD8+DC to antigen (cross-)presentation, an absolutely central process for the establishment of immune tolerance and generation of immunity, could not be assessed to date due to the lack of suitable experimental systems. Numerous data, however, point to a pivotal role of these CD8+DC in the development of a cytotoxic response to viruses, intracellular bacteria, and certain tumors. Based on the identification of a surface receptor, which is exclusively expressed in cross-presenting CD8+DC, we will be able to genetically delete these DC in mice and thus define their role in the immune system at steady state (tolerance) and in infection (immunity). These studies will be accompanied by numerous approaches aimed at defining the function of CD8+ DC in various organs of wild type mice. At the same time, we will identify the human counterpart of murine CD8+DC. These human DC will be phenotypically characterized and functionally tested, in particular for their capacity to (cross-)present antigen to CD8+ T cells, which are the mainstay of the cytotoxic immune defense. These basic studies will provide information which may enable us in the future to develop fundamentally new types of vaccines optimized for the induction of cytotoxic T cells directed against viral diseases and tumors.