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

Matthias Schaier; Angele Leick; Lorenz Uhlmann; Florian Kälble; Christian Morath; Volker Eckstein; Anthony Ho; Carsten Mueller-Tidow; Stefan Meuer; Karsten Mahnke; Claudia Sommerer; Martin Zeier; Andrea Steinborn

doi:10.1111/imm.12947

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

Immunology. 2018 Oct;155(2):211-224. doi: 10.1111/imm.12947. Epub 2018 May 25.

Authors

Affiliations

¹ Department of Medicine I (Nephrology), University of Heidelberg, Heidelberg, Germany.
² Department of Obstetrics and Gynaecology, University of Heidelberg, Heidelberg, Germany.
³ Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
⁴ Department of Medicine V (Haematology), University of Heidelberg, Heidelberg, Germany.
⁵ Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
⁶ Department of Dermatology, University of Heidelberg, Heidelberg, Germany.

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.

Keywords: T-cell differentiation; end-stage renal disease; immunosenescence; regulatory T cells; renal replacement therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Biomarkers
CD4-Positive T-Lymphocytes / cytology*
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Cell Differentiation*
Comorbidity
Female
Humans
Immunophenotyping
Inducible T-Cell Co-Stimulator Protein / metabolism
Kidney Failure, Chronic / immunology*
Kidney Failure, Chronic / therapy*
Kidney Transplantation*
Lymphocyte Activation / immunology
Male
Middle Aged
Renal Dialysis*
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
Young Adult

Substances

Biomarkers
ICOS protein, human
Inducible T-Cell Co-Stimulator Protein