TY  - JOUR
AU  - Wißfeld, Jannis
AU  - Hering, Marvin
AU  - ten Bosch, Nora
AU  - Cui, Guoliang
TI  - The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells.
JO  - European journal of immunology
VL  - 54
IS  - 7
SN  - 0014-2980
CY  - Weinheim
PB  - Wiley-VCH
M1  - DKFZ-2024-00854
SP  - e2350825
PY  - 2024
N1  - #EA:D192#LA:D192# / 2024 Jul;54(7):e2350825 / HI-TRON
AB  - 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.
KW  - AKT (Other)
KW  - CD8+ (Other)
KW  - CsA (Other)
KW  - Ribosomal protein S6 (Other)
KW  - T cells (Other)
KW  - mTOR (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38650034
DO  - DOI:10.1002/eji.202350825
UR  - https://inrepo02.dkfz.de/record/289672
ER  -