Different mechanisms of cardiac allograft rejection in wildtype and CD28-deficient mice

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 allo-antigen 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.