Deep phenotyping of T cell populations under long‐term treatment of tacrolimus and rapamycin in patients receiving renal transplantations by mass cytometry

Tacrolimus (FK506) and rapamycin (RAPA) are widely used to maintain long‐term immunosuppression after organ transplantation. However, the impact of accumulative drug administration on the recipients’ immune systems remains unclear. We investigated the impact of 3‐year FK506 or RAPA treatment after renal transplantation on the human immune systems. A discovery cohort of 30 patients was first recruited, and we discovered two distinctive T lineage suppressive regulatory patterns induced by chronic treatment of FK506 and RAPA. The increased percentage of senescent CD8(+)CD57(+) T lineages and less responsive T cell receptor (TCR) pathway in the FK506 group indicate better graft acceptance. Meanwhile, percentages of regulatory T cells (Tregs) and expression of CTLA‐4 were both up to two‐fold higher in the RAPA group, suggesting the inconsistent reactivation potential of the FK506 and RAPA groups when an anti‐tumour or anti‐infection immune response is concerned. Additionally, up‐regulation of phosphorylated signaling proteins in T lineages after in vitro CD3/CD28 stimulation suggested more sensitive TCR‐signaling pathways reserved in the RAPA group. An independent validation cohort of 100 renal transplantation patients was further investigated for the hypothesis that long‐term RAPA administration mitigates the development of tumours and infections during long‐term intake of immunosuppressants. Our results indicate that RAPA administration indeed results in less clinical oncogenesis and infection. The deep phenotyping of T‐cell lineages, as educated by the long‐term treatment of different immunosuppressants, provides new evidence for personalized precision medicine after renal transplantations.