The role of Staphylococcus aureus in transplantation tolerance

Bacterial infections are frequently encountered in the peri-operative period, and clinical correlations between bacterial infections and rejection have been proposed. However, the effect of bacterial infections in transplantation tolerance has not been well characterized. We hypothesize that innate immune recognition of bacterial antigens can stimulate adaptive T cell responses that result in the inhibition of tolerance induction. We hypothesize that innate immune recognition of bacterial antigens can stimulate early cytokine responses, leading to bystander T cell activation and increased alloreactivity, thereby prohibiting tolerance induction. To test this hypothesis, we used the model organism Staphylococcus aureus (SA), a frequently encountered Gram-positive, extracellular bacterium responsible for a variety of infectious events in the perioperative period. We observed that intraperitoneal SA infection at the time of transplantation prevents skin allograft tolerance induction by anti-CD154 and donor-specific transfusion (DST) in mice whereas SA infection did not prevent the acceptance of syngeneic skin grafts. Prevention of tolerance induction by SA was associated with a T cell-dependent rejection process, as SA infection of Rag-deficient and TCRbetadelta-deficient recipients did not precipitate skin allograft rejection. Following infection, SA induces the acute production of IL-6, which is critically important for the development of the alloreactive T cell response, as infection-induced rejection is abrogated in IL-6-deficient recipients. Furthermore, IL-6 alone is sufficient to prevent skin allograft tolerance induction. Mechanistically, SA-induced IL-6 promotes the CD154-independent proliferation of alloreactive CD4 and CD8 T cells and is associated with the presence of primed IFNgamma-producing, but not IL-17-producing alloreactive T cells in the lymph nodes and spleen upon rejection. Taken together, these results support a hypothesis that SA-induced IL-6 inhibits the development of skin allograft tolerance by augmenting the CD154-independent activation and proliferation of alloreactive T cells, leading to an imbalance between effector and regulatory T cells resulting in a resistance to suppression.;In addition to early innate immune activation and induction of proinflammatory cytokines, several viruses and bacteria, including SA, encode superantigens, which may have direct effects on alloreactive T cell populations. We hypothesize that perturbation of the alloreactive T cell repertoire by superantigens can negatively impact transplantation tolerance. To test this hypothesis, we used purified Staphylococcal enterotoxin A (SEA) at the time of transplantation and tolerance induction. In the absence of infection, SEA also prevented the induction of transplantation tolerance; however, SEA administration was associated with significantly lower IL-6 production than SA infection and IL-6 was not necessary for SEA-induced rejection. Rather, SEA administration was associated with deletion of the relevant Vbeta populations than. This deletion is independent of IL-6. These data led us to hypothesize that superantigen-induced prevention of skin allograft acceptance may be more dependent on direct effects on the alloreactive T cell repertoire, possibly via homeostatic deletion induced expansion of alloreactive precursors at the time of transplantation and tolerance induction.