CD40-CD40 ligand-independent activation of CD8+ T cells can trigger allograft rejection

In experimental transplantation, blockade of CD40-CD40 ligand (CD40L) interactions has proved effective at permitting longterm graft survival and has recently been approved for clinical evaluation. We show that CD4(+) T cell-mediated rejection is prevented by anti-CD40L mAb therapy but that CD8(+) T cells remain fully functional. Furthermore, blocking CD40L interactions has no effect on CD8(+) T cell activation, proliferation, differentiation, homing to the target allograft, or cytokine production. We conclude that CD40L is not an important costimulatory molecule for CD8(+) T cell activation and that following transplantation donor APC can activate recipient CD8(+) T cells directly without first being primed by CD4(+) T cells.