Regulation of epithelial propeties in Langerhans cells

Environment-exposed epithelial tissues of various organs contain networks of resident leukocytes known as Langerhans-type dendritic cells (LCs). LCs play a central role within the immune system as they are the most immediate recipients of exogenous antigens. Their localization within epithelial tissue and thus their presence in vivo depends on E-cadherin-mediated cell adhesion of LCs to epithelial cells. Immature LCs egress from epithelia either spontaneously or in response to inflammatory signals and matureate while they migrate to T-cell areas of lymphoid organs. According to specific signals that LCs receive from the epithelial environment they exert tolerogenic or immunogenic functions after maturation. A disruption of these functions may cause autoimmune inflammatory disorders. Apart from that, LCs also exert important innate immune functions and regulate the homeostasis of epithelial tissues. LC-type DCs are unique among the DC-family because they are specialized to perform immune function within the epithelium by expressing epithelial adhesion molecules (such as E-cadherin, Claudin1) which are otherwise restricted to cells of non-hematopoietic origin. The dynamic regulation of these epithelial-type adhesive properties of LCs is critical for their epithelial localization and LC egression from the skin upon activation. One important question we ask in this proposal is therefore, how hematopoietic LC precursors adopt these epithelial features and how they are down-regulated upon LC activation. In a genome wide analysis for TGF-b1-regulated genes during LC differentiation, we identified multiple epithelial genes including epithelia- associated transcription factors that are up-regulated upon TGF-b1 in LC precursors. In this proposal, I aim to elucidate the transcriptional regulators that control the dynamic changes of epithelial properties during LC differentiation and maturation. The specific aims are to: Aim1: Identify the transcriptional regulators that induce an epithelial programme downstream of TGF-b1 signalling during LC differentiation Aim2: Elucidate the role of EMT-signalling, which is known to regulate the transition of epithelial to mesenchymal cells during embryonic development in the context of LC maturation Aim3: Establish an organotypic epidermal co-culture model to study the impact of Keratinocytes on LC development and function For functional studies, I will apply a retroviral gene expression system that allows to dissect the signalling machinery controlling epithelial genes in LCs. Subsequently, I will determine the impact of these signals on LC function in T-cell stimulation assays. This work will contribute to a better understanding of cellular mechanisms underlying epithelial immunity and tolerance.