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.

Dialysis patients have deficiencies regarding the generation of immune responses and show an increased susceptibility for infections. Persisting uremic conditions are made responsible for the increased aging of their immune system. In this study, we analyzed whether age-related differences in the differentiation of both recent-thymic-emigrant-(RTE)-regulatory (Tregs) and RTE-responder T cells (Tresps) into CD31-memory Tregs/Tresps led to differences in the suppressive activity of naive and memory Tregs on autologous Tresps between healthy volunteers and dialysis patients. We found that regardless of age, the differentiation of RTE-Treg/Tresps into CD31-memory-Treg/Tresps was significantly increased in dialysis patients. By analyzing the age-related differences in the differentiation of Tregs/Tresps, we saw that in healthy volunteers RTE-Tregs differentiate via CD31-memory Tregs into CD31-memory Tregs, which may strengthen the suppressive activity of the total Treg pool. In contrast RTE-Tresps of healthy volunteers differentiate via mature naive (MN)-Tresps into CD31-memory-Tresps, which may weaken the reactivity of the total Tresp pool. Our data revealed that this normal differentiation via MN-Tresps was lost in dialysis patients, suggesting that their Tresps are less sensitive to Treg-mediated immunosuppression. Functional analysis of Tregs on autologous Tresps showed an increasing suppressive activity with age in healthy individuals, who therefore may have a lower risk of developing autoimmune diseases but owing to decreased reactivity of their Tresps are more likely to suffer from infections. In contrast, dialysis patients exhibited a decreasing suppressive activity with age, owing to strengthened Tresp reactivity, which could explain the higher prevalence of chronic inflammatory conditions in these patients.

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