Oscillatory mTOR inhibition and T_reg increase in kidney transplantation

Intracellular metabolic pathways dependent upon the mammalian target of rapamycin (mTOR) play a key role in immune-tolerance control. In this study, we focused on long-term mTOR-dependent immune-modulating effects in kidney transplant recipients undergoing conversion from calcineurin inhibitors (CNI) to mTOR inhibitors (everolimus) in a 1-year follow-up. The conversion to everolimus is associated with a decrease of neutrophils and of CD8⁺ T cells. In addition, we observed a reduced production of interferon (IFN)-γ by CD8⁺ T cells and of interleukin (IL)-17 by CD4⁺ T lymphocytes. An increase in CD4⁺CD25⁺ forkhead box protein 3 (FoxP3)⁺ [regulatory T cell [(T_reg)] numbers was also seen. T_reg increase correlated with a higher proliferation rate of this regulatory subpopulation when compared with the CD4⁺FoxP3^- effector counterpart. Basal phosphorylation level of S6 kinase, a major mTOR-dependent molecular target, was substantially maintained in patients treated with everolimus. Moreover, oscillations in serum concentration of everolimus were associated with changes in basal and activation-dependent S6 kinase phosphorylation of CD4⁺ and CD8⁺ T cells. Indeed, T cell receptor (TCR) triggering was observed to induce significantly higher S6 kinase phosphorylation in the presence of lower everolimus serum concentrations. These results unveil the complex mTOR-dependent immune-metabolic network leading to long-term immune-modulation and might have relevance for novel therapeutic settings in kidney transplants.