h1

%0 Thesis
%A Hager, Fabian Tobias
%T Dynamics of homeostatic maturation and migration of intestinal dendritic cells
%I RWTH Aachen University
%V Dissertation
%C Aachen
%M RWTH-2024-04505
%P 1 Online-Ressource : Illustrationen
%D 2024
%Z Veröffentlicht auf dem Publikationsserver der RWTH Aachen University
%Z Dissertation, RWTH Aachen University, 2024
%X Dendritic cells (DCs) are the most important antigen-presenting cells (APCs) in the body that play a pivotal role in the induction of both immunogenic as well as tolerogenic adaptive immune responses. Central to these functions is their ability to sample their environment and subsequently migrate from peripheral tissues, via lymph, to lymph nodes, where they present peripherally acquired antigens to T cells. While DC migration can be induced by inflammatory stimuli, DCs continually migrate in the absence of overt inflammation, which is essential for the maintenance of peripheral tolerance. This has been best studied in the context of the intestine, where homeostatic DC migration is indispensable for the induction of tolerance to intestinal antigens, thereby preventing exaggerated immune responses such as chronic intestinal inflammation or food allergies. However, the signals and mechanisms that drive homeostatic DC migration remain largely unknown. Here, we examined the life cycle of small intestinal DCs using a range of approaches, including single-cell transcriptomics, photoconversion-based in vivo cell tracking, and multiparameter flow cytometry, to address how the maturation and subsequent migration of intestinal DCs is regulated. Using in vivo DC tracking combined with EdU incorporation, we show that small intestinal DCs proliferate in situ and, interestingly, are induced to proliferate upon tissue entry. Thereafter, DCs progressively lose their proliferative capacity along their maturation program, which is itself characterized by a gradual increase in surface MHCII as well as costimulatory molecules such as CD40 and CD86. Notably, we found that in the final stages of maturation, DCs share a common transcriptional program that is characterized by the upregulation of CCR7, apoptosis-associated genes and cell cycle arrest, regardless of their tissue of origin or subset. These findings suggest that the induction of migration is inherently linked to the DC maturation program and may therefore be regulated by highly conserved intrinsic pathways. Furthermore, our detailed quantification of the migration kinetics demonstrates that steady-state intestinal DC migration leads to an almost complete turnover of the migratory DC compartment of the mesenteric lymph node (MLN) every day. In addition, we utilize a bone marrow chimera system to reveal that the migration of intestinal cDC1s is inhibited by a cell-intrinsic lack of the metalloprotease ADAM10. Furthermore, we show that the migration of small intestinal CD103+ cDC2s is reduced by administration of the S1PR inhibitor FTY720, demonstrating that these pathways are selectively used by distinct DC subsets for the migration process. Taken together, our data provide novel insights into both the homeostatic maturation and migration of intestinal DCs, while also establishing key experimental systems for the analysis of molecular mechanisms regulating DC migration kinetics. Therefore, the data and tools presented here may aid in the development of drugs and vaccines aimed at enhancing the tolerogenic homeostatic migration of DCs to prevent or treat deleterious inflammatory responses, including allergies and autoimmune diseases.
%F PUB:(DE-HGF)11
%9 Dissertation / PhD Thesis
%R 10.18154/RWTH-2024-04505
%U https://publications.rwth-aachen.de/record/985175