Mapping the phenotype and functions of antigen-presenting cells (APCs) during CNS autoimmunity

几种髓系细胞可在中枢神经系统自身免疫过程中作为抗原呈递细胞（APCs）。然而，髓细胞亚群在体内的细胞类型特异性APC功能尚不清楚。因此，该项目将探索小胶质细胞、单核细胞来源的巨噬细胞和树突状细胞对多发性硬化症（MS）小鼠模型中致病性T细胞激活的相对贡献。我们希望使用基于A)荧光的命运定位方法来分离不同的抗原呈递细胞系，并进行全基因组转录组分析，以绘制疾病期间指定其致病功能的基因、途径和上游调节因子。接下来，B)细胞特异性基因靶向将用于选择性地消融髓细胞亚群的APC功能，以确定它们对致病性T细胞激活的相对贡献。最后，C)通过候选基因方法，探讨IKKa （IKK1）在中枢神经系统自身免疫过程中不同APCs中的作用。这些研究将为我们提供关于不同APCs在MS模型中的作用及其在疾病发病机制中的相对贡献的基本新信息。此外，我们将潜在地确定apc中的关键基因，途径和上游调节因子，这些可能代表MS治疗的新治疗靶点。

Several myeloid cells can act as antigen-presenting cells (APCs) during CNS autoimmunity. However, the cell type specific APC functions of myeloid cell subsets in vivo are unclear. This project will therefore explore the relative contribution of microglia, monocyte-derived macrophages and dendritic cells for the activation of pathogenic T cells in a mouse model of multiple sclerosis (MS). We want to use A) fluorescence-based fate-mapping approaches to isolate different antigen-presenting cell lineages and perform genome-wide transcriptome analysis to map genes, pathways and upstream regulators that specify their pathogenic functions during disease. Next, B) cell specific gene targeting will be applied to selectively ablate the APC function of myeloid cell subsets to determine their relative contribution for the activation of pathogenic T cells. Finally, C) by using a candidate gene approach, the role of IKKa (IKK1) in different APCs during CNS autoimmunity will be explored. These studies will give us fundamental new information about the role of different APCs in MS models and their relative contributions to disease pathogenesis. In addition, we will potentially identify critical genes, pathways and upstream regulators in APCs that may represent new therapeutic targets in the treatment of MS.