Terminally differentiated CD8+ Temra cells are associated with the risk for acute kidney allograft rejection

Abstract

Background: End-stage renal disease (ESRD) is associated with T-cell dysregulation, leading to a variable degree of lymphopenia and increased T-cell differentiation. This may cause a relevant reduction in T-cell immunity, yielding a lowered risk for acute rejection (AR) of kidney allografts.

Methods: Before kidney transplantation, circulating CD4 and CD8 T-cell differentiation was established by determining the frequency of naive T cells, central memory and effector memory T cells, and the highly differentiated CD8 Temra cells. In addition, the frequency of differentiated T cells without expression of the costimulatory molecule CD28 was measured.

Results: In 47 patients of the 185 patients included, a biopsy-proven AR occurred. Compared with healthy controls, T cells of patients with ESRD were significantly more differentiated. Patients with AR showed the least signs of T-cell dysregulation with significantly more T cells, more naive T cells, and less terminal differentiation of memory T cells compared with nonrejecting patients. After multivariate analysis, only the frequency of terminally differentiated CD8 Temra cells (per percent, 4% decrease of risk [P=0.006]; per tertile, 34% decrease in risk [P=0.002]) and the number of human leukocyte antigen mismatches (per mismatch, 33% [P=0.005]) predicted the risk for AR. Functional analysis showed that CD8 Temra cells have a highly proinflammatory and cytotoxic profile. In vitro T-cell proliferation assays did not reveal a suppressor function of these cells.

Conclusions: Advanced ESRD-related T-cell dysregulation that is associated with a relative increase of terminally differentiated CD8 Temra cells protects against AR after kidney transplantation.