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000289672 1001_ $$0P:(DE-He78)8cec0c3cf0d3118bc2af6551facf9536$$aWißfeld, Jannis$$b0$$eFirst author$$udkfz
000289672 245__ $$aThe immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells.
000289672 260__ $$aWeinheim$$bWiley-VCH$$c2024
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000289672 520__ $$aCyclosporin 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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000289672 650_7 $$2Other$$aAKT
000289672 650_7 $$2Other$$aCD8+
000289672 650_7 $$2Other$$aCsA
000289672 650_7 $$2Other$$aRibosomal protein S6
000289672 650_7 $$2Other$$aT cells
000289672 650_7 $$2Other$$amTOR
000289672 7001_ $$0P:(DE-He78)b099c4255c1bff642f4d338ef157596e$$aHering, Marvin$$b1$$udkfz
000289672 7001_ $$0P:(DE-He78)ad4b5f19b891aeb51245ce42ff3d92ff$$aten Bosch, Nora$$b2
000289672 7001_ $$0P:(DE-He78)0b7ce76033a6756b91f5bfb12602e20b$$aCui, Guoliang$$b3$$eLast author$$udkfz
000289672 773__ $$0PERI:(DE-600)1491907-2$$a10.1002/eji.202350825$$gp. 2350825$$n7$$pe2350825$$tEuropean journal of immunology$$v54$$x0014-2980$$y2024
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