Home > Publications database > The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells. > print

001     289672
005     20250731135155.0
024 7 _ |a 10.1002/eji.202350825
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037 _ _ |a DKFZ-2024-00854
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Wißfeld, Jannis
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245 _ _ |a The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells.
260 _ _ |a Weinheim
|c 2024
|b Wiley-VCH
336 7 _ |a article
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520 _ _ |a Cyclosporin A is a well-established immunosuppressive drug used to treat or prevent graft-versus-host disease, the rejection of organ transplants, autoimmune disorders, and leukemia. It exerts its immunosuppressive effects by inhibiting calcineurin-mediated dephosphorylation of the nuclear factor of activated T cells (NFAT), thus preventing its nuclear entry and suppressing T cell activation. Here we report an unexpected immunostimulatory effect of cyclosporin A in activating the mammalian target of rapamycin complex 1 (mTORC1), a crucial metabolic hub required for T cell activation. Through screening a panel of tool compounds known to regulate mTORC1 activation, we found that cyclosporin A activated mTORC1 in CD8+ T cells in a 3-phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB/AKT)-dependent manner. Mechanistically, cyclosporin A inhibited the calcineurin-mediated AKT dephosphorylation, thereby stabilizing mTORC1 signaling. Cyclosporin A synergized with mTORC1 pathway inhibitors, leading to potent suppression of proliferation and cytokine production in CD8+ T cells and an increase in the killing of acute T cell leukemia cells. Consequently, relying solely on CsA is insufficient to achieve optimal therapeutic outcomes. It is necessary to simultaneously target both the calcineurin-NFAT pathway and the mTORC1 pathway to maximize therapeutic efficacy.
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650 _ 7 |a AKT
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650 _ 7 |a CD8+
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650 _ 7 |a CsA
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650 _ 7 |a Ribosomal protein S6
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650 _ 7 |a T cells
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650 _ 7 |a mTOR
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700 1 _ |a Hering, Marvin
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700 1 _ |a ten Bosch, Nora
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700 1 _ |a Cui, Guoliang
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773 _ _ |a 10.1002/eji.202350825
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|t European journal of immunology
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856 4 _ |u https://inrepo02.dkfz.de/record/289672/files/Eur%20J%20Immunol%20-%202024%20-%20Wi%C3%9Ffeld%20-%20The%20immunosuppressive%20drug%20cyclosporin%20A%20has%20an%20immunostimulatory%20function%20in%20CD8%20T%20cells.pdf
856 4 _ |u https://inrepo02.dkfz.de/record/289672/files/Eur%20J%20Immunol%20-%202024%20-%20Wi%C3%9Ffeld%20-%20The%20immunosuppressive%20drug%20cyclosporin%20A%20has%20an%20immunostimulatory%20function%20in%20CD8%20T%20cells.pdf?subformat=pdfa
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