A new T-cell receptor transgenic model of the CD4+ direct pathway:: Level of priming determines acute versus chronic rejection

Background. T-cell receptor transgenic (TCR-tg) mouse models with direct CD4(+) alloreactivity will help elucidate mechanisms of transplant rejection and tolerance in vivo. Although such models exist, they are limited by unusual strain combinations or are based on model antigens. Methods. A TCR-tg mouse with direct CD4 specificity in the widely used BALB/c donor -> C57BL/6 host strain combination was created. This TCR-tg mouse, named 4C, was selected for reactivity against BALB/c dendritic cells in order to model early priming events after transplantation. The response of 4C T cells to skin and heart transplants were characterized. Results. The alloantigen is restricted by I-A(d) and appears to be widely distributed in mouse tissues. 4C T cells are able to acutely reject skin but not heart allografts. Paradoxically, heart grafts elicited a stronger proliferation and effector function of TCR-tg T cells than skin grafts. 4C T cells caused cardiac allograft vasculopathy in the absence of other T cells and alloantibodies, suggesting a role for the direct pathway in chronic rejection. Augmentation of priming with an infusion of donor-derived dendritic cells resulted in acute heart allograft rejection by 4C T cells, demonstrating that the level of priming can play a role in determining acute versus chronic rejection by the CD4 direct pathway. Conclusions. Rejection of a graft by the direct CD4 pathway is determined by graft susceptibility to rejection, as well as the degree of T-cell priming caused by the graft. Grafts that are not acutely rejected can develop transplant vasculopathy mediated by the direct CD4(+) T cells.