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@ARTICLE{Wifeld:289672,
      author       = {J. Wißfeld$^*$ and M. Hering$^*$ and N. ten Bosch$^*$ and
                      G. Cui$^*$},
      title        = {{T}he immunosuppressive drug cyclosporin {A} has an
                      immunostimulatory function in {CD}8+ {T} cells.},
      journal      = {European journal of immunology},
      volume       = {54},
      number       = {7},
      issn         = {0014-2980},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DKFZ-2024-00854},
      pages        = {e2350825},
      year         = {2024},
      note         = {#EA:D192#LA:D192# / 2024 Jul;54(7):e2350825 / HI-TRON},
      abstract     = {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.},
      keywords     = {AKT (Other) / CD8+ (Other) / CsA (Other) / Ribosomal
                      protein S6 (Other) / T cells (Other) / mTOR (Other)},
      cin          = {D192 / A370},
      ddc          = {610},
      cid          = {I:(DE-He78)D192-20160331 / I:(DE-He78)A370-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38650034},
      doi          = {10.1002/eji.202350825},
      url          = {https://inrepo02.dkfz.de/record/289672},
}