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

Abstract

AbstractCyclosporin 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.