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@PHDTHESIS{Hager:985175,
      author       = {Hager, Fabian Tobias},
      othercontributors = {Pabst, Oliver and Zenke, Martin and Panstruga, Ralph},
      title        = {{D}ynamics of homeostatic maturation and migration of
                      intestinal dendritic cells},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2024-04505},
      pages        = {1 Online-Ressource : Illustrationen},
      year         = {2024},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, RWTH Aachen University, 2024},
      abstract     = {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.},
      cin          = {526000-2 ; 922310 / 160000},
      ddc          = {570},
      cid          = {$I:(DE-82)526000-2_20140620$ / $I:(DE-82)160000_20140620$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2024-04505},
      url          = {https://publications.rwth-aachen.de/record/985175},
}