Regulatory T cells can prevent memory CD8 super(+) T-cell-mediated rejection following polymorphonuclear cell depletion

Accumulating evidence suggests that alloreactive memory T cells (Tm) may form a barrier to tolerance induction in large animals and humans due in part to a resistance to suppression by Treg. However, why Tm are resistant to regulation and how the Tm response to an allograft differs from that of naive T cells, which are amenable to suppression by Treg, remains unknown. Here, we show that accelerated graft rejection mediated by CD8 super(+) Tm was due to the enhanced recruitment of PMN to allografts in a mouse skin allograft model. Importantly, depletion of PMN slowed the kinetics of (but did not prevent) rejection mediated by Tm and created a window of opportunity that allowed subsequent suppression of rejection by Treg. Taken together, we conclude that CD8 super(+) Tm are not intrinsically resistant to suppression by Treg but may rapidly inflict substantial graft damage before the establishment of regulatory mechanisms. These data suggest that if Tm responses can be attenuated transiently following transplantation, Treg may be able to maintain tolerance through the suppression of both memory and naive alloreactive T-cell responses in the long term.