Immunological memory has evolved to protect against repeated infections, but it also develops to other foreign antigens and thus is a liability for transplantation. Early transplantation experiments showed T cell-dependent accelerated rejection of secondary skin transplants following rejection of primary grafts. Methods to circumvent memory cell function or generation are highly sought after in transplantation because memory cells, once they are generated, are more difficult to control with current immunosuppressive therapies. Our data show that mice that have rejected previously long-term accepted cardiac allografts following infection with Listeria monocytogenes accept second donor heart grafts after the infection is cleared in the absence of any immunosuppression. This challenges the prevailing paradigm of immunological memory of rejection, and instead supports one of memory of tolerance. Interestingly, even though these mice lack a memory of rejection, they retain protective immunity to Listeria and survive when rechallenged with a lethal Listeria infection. Maintenance of tolerance in these transplanted mice prior to infection was characterized by high percentages of intra-graft regulatory T cells and effector T cells that expressed the inhibitory receptor PD-1. However, only in the presence of increased alloreactive cell precursor frequencies did combined blockade of these two pathways precipitate rejection. Listeria infection transiently increased graft-infiltrating cells and lowered percentages of regulatory cells and PD-1+ cells in the primary graft. However, both of these latter populations reappeared in high percentages in the second tolerated grafts. The restored tolerance in the second grafts was dependent on regulatory cells and signals from PD-L1, as blockade of either of these pathways was sufficient to precipitate rejection of the second tolerated graft. These data support a model in which a dominant memory of tolerance exists to reestablish a tolerant state following infection-mediated rejection. These observations reveal an unexpected resilience of regulatory tolerance and expand on the rules of allo-sensitization established by Medawar and colleagues almost 70 years ago. They also identify potential checkpoints for enforcing transplantation tolerance during infections.

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