Polyfunctional donor-reactive T cells are associated with acute T-cell mediated rejection of the kidney transplant.

Abstract

Acute T-cell mediated rejection (aTCMR) still remains a clinical problem after kidney transplantation despite significant improvements in immunosuppressive regimens. Polyfunctional T-cells, i.e. T-cells producing multiple pro-inflammatory cytokines, are believed to be the most relevant T-cells in an immune response. The aim of this study was to determine whether polyfunctional donor-reactive T-cells are associated with aTCMR. In a case-control study, 49 kidney transplant recipients with a biopsy-proven aTCMR in the first year after transplantation were included, as well as 51 controls without aTCMR. Circulating donor-reactive T-cells were identified by the expression of CD137 after short-term co-culture with donor antigen-presenting cells. Polyfunctional donor-reactive T-cells were further characterized by dissection into different T-cell subsets encompassing the spectrum of naïve to terminally-differentiated effector T-cells. Prior to kidney transplantation, proportions of donor-reactive CD4+ (0.03% versus 0.02%; P<0.01) and CD8+ (0.18% versus 0.10%; P<0.01) CD137++ T-cells were significantly higher in recipients with a biopsy-proven aTCMR versus non-rejectors. Polyfunctionality was higher (P=0.03) in this subset of CD137-expressing T-cells. These cells were predominantly of the EM/EMRA-phenotype, with polyfunctional donor-reactive CD137++CD4+ T-cells predominantly co-expressing CD28 whereas approximately half of the polyfunctional CD137++CD8+ T-cells co-expressed CD28. In addition, at the time of aTCMR, polyfunctional donor-reactive CD137++ CD4+, but not CD8+, T-cells, were specifically decreased by 75% compared to before transplantation in recipients with as well as those without an aTCMR. Prior to transplantation, the proportion of polyfunctional donor-reactive CD137++ T-cells is associated with the occurrence of a biopsy-proven aTCMR within the first year after transplantation.