Modulation of Dendritic Cell Behaviour

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BRUCKNER, Markus, 2011. Modulation of Dendritic Cell Behaviour [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Bruckner2011Modul-16047, title={Modulation of Dendritic Cell Behaviour}, year={2011}, author={Bruckner, Markus}, address={Konstanz}, school={Universität Konstanz} }

2011 Modulation dendritischen Zellverhaltens Bruckner, Markus Bruckner, Markus Dendritic cells (DCs) are professional antigen-presenting cells (APCs) capable of inducing immunity or mediating tolerance. Given their role as sentinels of the immune system, DCs are predominantly located in peripheral tissues and acquire antigenic information from their surrounding which are required for the education of the adaptive immune system. After acquiring antigenic information, DCs mature and up-regulate the chemokine receptor CCR7 required for their guidance into lymphatic tissues along cues of the CCR7-ligands CCL19 and CCL21 to induce antigen-specific T cell responses. The environment in which DCs undergo maturation determines in particular their migratory as well as their T cell stimulatory capacity and hence designates the outcome of the immune response. The lipid mediator Prostaglandin E2 (PGE2), which is increasingly produced under inflammatory conditions, was described to modulate important DC functions such as efficient DC migration, T cell activation and cytokine production in health and disease. Since DCs become evident to play key roles in many diseases and can be exploited for clinical immunotherapy, the understanding of their functions and its modulation is of great interest. Therefore, the present thesis addressed the potential of PGE2 in modulating distinct aspects of DC behaviour.<br /><br />In inflammation, DCs orchestrate immune responses by recruiting immune cells to sites of inflammation or in lymphoid tissues through the release of specific attractants, so-called chemokines. A comprehensive study in this thesis addressed the impact of PGE2 on the expression of a wide range of chemokines in DCs revealing that PGE2 decisively alters the chemokine expression pattern of DCs and thus their role in orchestrating immune responses in health and disease.<br />Moreover, PGE2 is known to augment the T cell stimulatory capacity of DCs, however, there is paucity of knowledge about the precise mechanisms. Investigations on the T cell stimulatory capacity of DCs revealed that PGE2 induced surface expression of the co-stimulatory molecules OX40L, CD70 and 4-1BBL on DCs and thereby augmented DC-mediated specific T cell responses. The observed PGE2-mediated expression of OX40L on DCs not only offers new opportunities in the design of DC-based cancer immunotherapy, it also provides novel insights in the regulation of PGE2-mediated autoimmune diseases in which DCs participate in disease development.<br />Besides PGE2, distinct lipids derived from the sterol metabolism have recently become evident to modulate DC migration. Tumour-derived sterol metabolites were described to impair the ability of DCs to migrate into secondary lymphatic organs (SLOs) in a nuclear liver X receptor (LXR)-dependent manner. This thesis provides evidence that PGE2 counteracts nuclear LXR activation and suppression of DC migration. These results support the feasibility of treating PGE2-mediated autoimmunity with synthetic LXR agonists.<br />Furthermore, this thesis unravels a mechanism explaining how DCs may swarm into T cell zones of SLOs. The herein performed studies on the migratory behaviour of DCs towards SLO-derived chemokines demonstrate that adhesive random DC migration along surfaces is triggered via surface-immobilized CCL21, whereas directionality is guided by CCL19 or solubilized CCL21. Intriguingly, DCs were found to solubilize surface-bound CCL21 to induce their own directional guidance cues allowing their directed migration along pre-defined tracks of immobilized CCL21.<br />Taken together, the present thesis provides new insights in modulating DC functions such as DC migration, T cell activation and cytokine secretion with valuable implications in health and disease. 2013-09-15T22:25:03Z 2011-11-03T11:48:07Z eng terms-of-use Modulation of Dendritic Cell Behaviour

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