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

Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28(-) T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4(+)CD57(+)programmed death 1 (PD-1)(-) T cells pretransplantation 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 fluorescence activated cell sorted (FACS) CD4(+)CD57(+)PD-1(-) and CD8(+)CD57(+)PD-1(-) T cells, and their CD57(-) control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation 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 up-regulation of CD244 and PD-1 was observed for CD4(+)CD57(-)PD-1(-) T cells after allogeneic stimulation, but no up-regulation 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<001) and CD8(+)CD57(+)PD-1(-) T cells (median of inhibition 10%, P<005). 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 inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.