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.

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