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T cell receptor transgenic (TCR-Tg) T cells are often used as tracer populations of antigen-specific responses to extrapolate findings to endogenous T cells. The extent to which TCR-Tg T cells behave purely as tracer cells or modify the endogenous immune response is not clear. To test the impact of TCR-Tg T cell transfer on endogenous alloimmunity, recipient mice were seeded with CD4+or CD8+TCR-Tg or polyclonal T cells at the time of cardiac allograft transplantation. Only CD4+TCR-Tg T cells accelerated rejection and, unexpectedly, led to a dose-dependent decrease in both transferred and endogenous T cells infiltrating the graft. In contrast, recipients of CD4+TCR-Tg T cells exhibited enhanced endogenous donor-specific CD8+T cell activation in the spleen and accelerated alloantibody production. Introduction of CD4+TCR-Tg T cells also perturbed the intragraft accumulation of innate cell populations. Transferred CD4+TCR-Tg T cells alter many aspects of endogenous alloimmunity, suggesting that caution should be used when interpreting experiments using these adoptively transferred cells because the overall nature of allograft rejection may be altered. These results also may have implications for adoptive CD4+T cell immunotherapy in tumor and infectious clinical settings because cell infusion may have additional effects on natural immune responses.

Clinical correlations between bacterial infections and rejection suggest a hypothesis that innate immune stimulation by bacterial infections results in the production of inflammatory cytokine that facilitate bystander T‐cell activation, increased alloreactivity and inhibition of tolerance induction. Previous studies demonstrated that IFNβ produced during an infection with a model bacterium, Listeria monocytogenes, prevented the induction of transplantation tolerance in mice with anti‐CD154 and donor‐specific transfusion (DST) (1). We investigated the impact of two clinically relevant bacterial infections at the time of transplantation on the ability of anti‐CD154 and DST to induce skin allograft acceptance in mice. Staphylococcus aureus(SA) infection prevented skin allograft acceptance whereas maximally tolerated doses of Pseudomonas aeruginosainfection had no effect. SA induced an acute production of IL‐6, which was necessary and sufficient for the prevention of skin allograft acceptance. Furthermore, a single pulse of methylprednisolone modulated IL‐6 production during SA infection and facilitated skin allograft acceptance in SA‐infected recipients. Taken together, our results suggest that bacterial infections elicit specific proinflammatory cytokines signatures that can serve as barriers to tolerance induction, and that inhibiting the production of or neutralizing these inflammatory cytokines can synergize with costimulatory blockade‐based therapies to facilitate the development of transplantation tolerance.

T cells play a major role in the acute rejection of transplanted organs. Using mice transgenic for a T-cell-restricted NF-?B super-repressor (I?B??N-Tg mice), we have previously shown that T-cell-NF-?B is essential for the acute rejection of cardiac but not skin allografts. In this study, we investigated the mechanism by which skin grafts activate I?B??N-Tg T cells. Rejection was not due to residual T-cell-NF-?B activity as mice with p50p52??T cells successfully rejected skin grafts. Rather, skin but not cardiac allografts effectively induced proliferation of graft-specific I?B??N-Tg T cells. Rejection of skin grafts by I?B??N-Tg mice was in part dependent on the presence of donor Langerhans cells (LC), a type of epidermal dendritic cells (DC), as lack of LC in donor skin grafts resulted in prolongation of skin allograft survival and injection of LC at the time of cardiac transplantation was sufficient to promote cardiac allograft rejection by I?B??N-Tg mice. Our results suggest that LC allow NF-?B-impaired T cells to reach an activation threshold sufficient for transplant rejection. The combined blockade of T-cell-NF-?B with that of alternative pathways allowing activation of NF-?B-impaired T cells may be an effective strategy for tolerance induction to highly immunogenic organs.

Although CD28 blockade results in long-term cardiac allograft survival in wildtype mice, CD28-deficient mice effectively reject heart allografts. This study compared the mechanisms of allogeneic responses in wildtype and CD28-deficient mice. Adoptive transfer of purified CD28-deficient T cells into transplanted nude mice resulted in graft rejection. However, this model demonstrated that the allogeneic T cell function was severely impaired when compared with wildtype T cells, despite similar survival kinetics. Cardiac allograft rejection depended on both CD4⁺ and CD8⁺ T cell subsets in CD28-deficient mice, whereas only CD4⁺ T cells were necessary in wildtype recipients. These results suggested that CD8⁺ T cells were more important in CD28-deficient than wildtype mice. In addition to the CD8⁺ T cell requirement, allograft rejection in CD28-deficient mice was dependent on a sustained presence of CD4⁺ T cells, whereas it only required the initial presence of CD4⁺ T cells in wildtype mice. Taken together, these data suggest that CD4⁺ T cells from CD28-deficient mice have impaired responses to alloantigen in vivo, thus requiring long-lasting cooperation with CD8⁺ T cell responses to facilitate graft rejection. These results may help to explain the failure to promote graft tolerance in some preclinical and clinical settings.