End-stage renal disease, dialysis, kidney transplantation and their impact on CD4 + T-cell differentiation.

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.
(© 2018 John Wiley & Sons Ltd.)