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TY - THES AU - Jakobs, Jana TI - The role of zinc and calcium signals in T cell activation and differentiation PB - RWTH Aachen University VL - Dissertation CY - Aachen M1 - RWTH-2024-11014 SP - 1 Online-Ressource : Illustrationen PY - 2024 N1 - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University 2025 N1 - Dissertation, RWTH Aachen University, 2024 AB - 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. LB - PUB:(DE-HGF)11 DO - DOI:10.18154/RWTH-2024-11014 UR - https://publications.rwth-aachen.de/record/997053 ER -