Differential kinetics of effector and regulatory T cells in patients on calcineurin inhibitor–based drug regimens

Besides iatrogenic immunosuppression, endogenous suppression by regulatory T cells (Tregs) may also mediate inhibition of effector T cells after transplantation. Here we determined the effect of common immunosuppressive drug regimens on both Treg and effector T cells. Tregs and cytomegalovirus (CMV)-specific T cells were quantified in 88 renal transplant recipients, 58 hemodialysis patients, and 22 controls. T cell dynamics were longitudinally assessed within 20 weeks after transplantation. The number of Tregs was quantified by measurement of CD25 and/or FOXP3-positive cells and by functional assays. CMV-specific T cells were quantified by stimulation-induced intracellular cytokine analysis. Treg frequencies in transplant recipients were significantly lower compared to those in hemodialysis patients and controls. These lower Treg levels were associated with a less pronounced suppression of effector function. Treg levels decreased within the first weeks after transplantation and remained low in the long term. In contrast, although decreased at early post-transplant, long-term levels of CMV-specific T cells normalized to levels found in hemodialysis patients and controls. These studies suggest that there is an initial decrease of Tregs and effector T cells as a consequence of a direct inhibitory effect of immunosuppressive drugs. In the long term, persistently low Treg levels may favor normalization of effector T cells to ensure sufficient pathogen control.