The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells

• Verfasst von: Wißfeld, Jannis [VerfasserIn]
• Verfasst von: Hering, Marvin [VerfasserIn]
• Verfasst von: Bosch, Nora ten [VerfasserIn]
• Verfasst von: Cui, Guoliang [VerfasserIn]
• Titel: The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells
• Verf.angabe: Jannis Wißfeld, Marvin Hering, Nora ten Bosch and Guoliang Cui
• E-Jahr: 2024
• Jahr: July 2024
• Umfang: 9 S.
• Illustrationen: Diagramme
• Fussnoten: Das Pluszeichen im Titel ist hochgestellt ; Online veröffentlicht: 22. April 2024 ; Gesehen am 19.09.2024
• Titel Quelle: Enthalten in: European journal of immunology
• Ort Quelle: Weinheim : Wiley-VCH, 1971
• Jahr Quelle: 2024
• Band/Heft Quelle: 54(2024), 7 vom: Juli, Artikel-ID 2350825, Seite 1-9
• ISSN Quelle: 1521-4141
• DOI: doi:10.1002/eji.202350825
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: AKT
• Sach-SW: CD8+
• Sach-SW: CsA
• Sach-SW: mTOR
• Sach-SW: Ribosomal protein S6
• Sach-SW: T cells
• K10plus-PPN: 1903019044

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.