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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},
}
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