Oscillatory mTOR inhibition and Treg increase in kidney transplantation.

Intracellular metabolic pathways dependent on 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 one-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+ Foxp3+ (Treg) number was also seen. Treg 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.