Co-inhibitory profile and cytotoxicity of CD57+PD-1- T-cells in end stage renal disease patients

Summary

Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection as compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28^- T-cells, which express CD57, are not susceptible to belatacept treatment. High number of CD4⁺CD57⁺PD-1^- T-cells pre transplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of FACS-sorted CD4⁺CD57⁺PD-1^- and CD8⁺CD57⁺PD-1^- T-cells, and their CD57^- control populations, after allo antigen stimulation. The effect of belatacept on the cytotoxic capacity of pre-transplantation peripheral blood mononuclear cells from 20 patients who received belatacept post-transplantation was also tested. Expression of co-inhibitory molecule CD223 increased by approximately 10-fold after allogeneic stimulation in all four T-cell subsets. Proliferation and upregulation of CD244 and PD-1 was observed for CD4⁺CD57^-PD-1^- T-cells after allogeneic stimulation, but no upregulation of these markers occurred on CD8⁺ T-cells or CD4⁺CD57⁺PD-1^- T-cells. However, CD4⁺CD57⁺ PD-1^- T-cells and, to a lesser extent, CD8⁺CD57⁺PD-1^- T-cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4⁺CD57⁺PD-1^- T-cells (median of inhibition 31%, p<0.01) and CD8⁺CD57⁺PD-1^- T-cells (median of inhibition 10%, p<0.05).

In conclusion, alloantigen activated CD4⁺CD57⁺PD-1^- T-cells exhibited a less proliferative but more cytotoxic profile than their CD57^- counterparts. Their cytotoxic capacity can be partly inhibited by belatacept and was not associated with development of rejection after kidney transplantation. This article is protected by copyright. All rights reserved.