An individual's acquired immune history has been shown to influence the course of immune responses to future encounters with pathogens. T-cell memory elicited by infection with a specific virus can enhance the clearance of unrelated pathogens. However, this heterologous immunity might have other, more unfavourable consequences. Now, Adams et al. report in the Journal of Clinical Investigation that virus- induced memory T cells that are cross-reactive with donor alloantigens are a potent barrier to the induction of tolerance in transplant recipients. They propose that this is one potential explanation why strategies that effectively promote long-term allograft acceptance in specific pathogen-free rodents have been unsuccessful in non-human primate models and in human patients.

First, the authors showed that infection with virus results in the induction of virus-specific memory T cells that can also recognize foreign MHC molecules. They next tested whether the presence of this memory population could prevent tolerance induction using a protocol that has been shown to induce robust, life-long tolerance to fully MHC-mismatched skin grafts in naive mice. Indeed, mice that had previously been exposed to multiple viral infections were refractory to tolerance induction and rejected their allografts.

By adoptive-transfer experiments, they went on to show that the ability to resist tolerance induction was dependent on the dose of donor-specific memory T cells that were transferred to graft recipients. Contrary to expectation, CD8+ central memory T cells, as opposed to effector memory T cells, were the main mediators of rejection, indicating that these cells might have a lower threshold for activation. Finally, resistance to tolerance could be overcome when deoxyspergualin (DSG) — an inhibitor of nuclear factor-κB (NF-κB) translocation, which is a key event in T-cell activation — was included in the tolerance protocol.

In the light of these results, future strategies to induce tolerance in 'immune-experienced' patients should take into account the existence of allogeneic memory T cells.