Abstract
Premature aging of both CD4(+) regulatory T (Treg) and CD4(+) responder-T (Tresp) cells in patients with end-stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible T-cell co-stimulator-positive (ICOS(+) ) and ICOS(-) recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS(+) and ICOS(-) RTE Treg/Tresp cells into ICOS(+) CD31(-) or ICOS(-) CD31(-) memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS(+) and ICOS(-) Treg cells in co-culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS(+) RTE Treg/Tresp cells and ICOS(-) RTE Treg cells through CD31(+) memory Treg/Tresp cells into CD31(-) memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS(-) RTE Tresp cells showed an increased differentiation via ICOS(-) mature naive (MN) Tresp cells into CD31(-) memory Tresp cells. Thereby, the ratio of ICOS(+) Treg/ICOS(+) Tresp cells was not changed, whereas that of ICOS(-) Treg/ICOS(-) Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS(+) and ICOS(-) RTE Tresp cells proceeded, whereas that of ICOS(+) RTE Treg cells ceased and that of ICOS(-) RTE Treg cells switched to an increased differentiation via ICOS(-) MN Treg cells. Consequently, the ratios of ICOS(+) Treg/ICOS(+) Tresp cells and of ICOS(-) Treg/ICOS(-) Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS(+) and ICOS(-) Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long-term renal replacement therapy.