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@PHDTHESIS{Jakobs:997053,
      author       = {Jakobs, Jana},
      othercontributors = {Rink, Lothar and Ludwig, Andreas},
      title        = {{T}he role of zinc and calcium signals in {T} cell
                      activation and differentiation},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2024-11014},
      pages        = {1 Online-Ressource : Illustrationen},
      year         = {2024},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University 2025; Dissertation, RWTH Aachen University, 2024},
      abstract     = {This thesis aimed to examine the sources, kinetics, and
                      functions of zinc and calcium signals in T cell activation
                      and differentiation. Fast and homeostatic changes in zinc
                      and calcium concentrations after T cell activation were
                      investigated. Fast calcium signals were detected after the
                      activation of the CD3 protein complex, as previously well
                      described. After fast calcium signals, the homeostatic
                      calcium concentration remained low in activated cells. In
                      the case of zinc signaling, it was found that the activation
                      of the CD3 protein complex also specifically induces a rapid
                      zinc signal within a few minutes, while zinc signals were
                      not induced by the activation of costimulatory signals. In
                      contrast to calcium, a homeostatic zinc signal in activated
                      T cells was measured for up to 3 days. Since fast zinc and
                      calcium signals occur in parallel in T cell receptor
                      signaling the individual functions of zinc and calcium
                      signals have been distinguished. Zinc signaling was found to
                      upregulate the early T cell activation marker CD69, the
                      expression of IRF 1, and KLF-10. Calcium signals, on the
                      other hand, induced the expression of T-bet, and FoxP3, as
                      well as the release of IL-2 and to a lesser extent of
                      IFN-γ. Therefore, zinc and calcium signals affect the
                      induction of different proteins but act synergistically to
                      induce and regulate Th1 and Treg differentiation. Th1 cells
                      are regulated by IRF-1, via zinc signals, and T-bet, via
                      calcium signals, whereas Treg cells are regulated by KLF-10,
                      via zinc signals, and FoxP3, via calcium signals. Most
                      notably, the combination of zinc and calcium signals
                      resulted in substantially increased IFN-γ release and CD69
                      surface expression. In addition, it was demonstrated that
                      fast calcium signals affect zinc homeostasis. Calcium
                      signaling upregulated the zinc transporter Zip8 and Zip14,
                      which increased intracellular homeostatic zinc levels
                      necessary for calcium-induced IFN-γ expression. In contrast
                      to the individual effects on Th1 and Treg differentiation,
                      the differentiation into Th2 or Th17 cells was not induced
                      by zinc or calcium signals alone. Nevertheless, in T cells
                      activated by CD3 and CD28 stimulation, zinc reduced the
                      expression of IL-17 and thus indicates a suppressive
                      function on Th17 differentiation. Furthermore, zinc signals
                      were found to mimic the costimulatory effect of CD28 in
                      CD3-induced IFN-γ expression. These results highlight the
                      importance of the parallel occurrence of zinc and calcium
                      signals. This expands the understanding of T cell fate
                      decisions and enables targeted therapy options to influence
                      decisions of T cell differentiation.},
      cin          = {525501-2 ; 924820 / 160000},
      ddc          = {570},
      cid          = {$I:(DE-82)525501-2_20140620$ / $I:(DE-82)160000_20140620$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2024-11014},
      url          = {https://publications.rwth-aachen.de/record/997053},
}