Infection with the Intracellular Bacterium, Listeria monocytogenes, Overrides Established Tolerance in a Mouse Cardiac Allograft Model

Infections and TLR signals at the time of transplantation have been shown to prevent the induction of tolerance, but their effect on allografts after tolerance has been established is unclear. We here report that infection with Listeria monocytogenes precipitated the loss of tolerance and the MyD88- and T cell-dependent rejection of accepted cardiac allografts in mice. This loss of tolerance was associated with increases in the numbers of graft-infiltrating macrophages and dendritic cells, as well as CD4+FoxP3- and CD8+ T cells. Rejection was also associated with increased numbers of graft-infiltrating alloreactive as well as Listeria-reactive IFN gamma-producing T cells. Rejection of the established grafts required both IL-6 and IFN ss, cytokines produced during acute Listeria infection. However, IL-6 and IFN ss alone, even when present at higher concentrations than during Listeria infection, were insufficient to break tolerance, while the combination of IL-6 and IFN ss was sufficient to break tolerance. These and in vitro observations that IL-6 but not IFN ss enhanced T cell proliferation while IFN ss but not IL-6 enhanced IFN gamma production support a hypothesis that these cytokines play nonredundant roles. In conclusion, these studies demonstrate that the proinflammatory effects of infections can induce the loss of tolerance and acute rejection of accepted allografts.