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

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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.