T cells play a major role in the acute rejection of transplanted organs. Using mice transgenic for a T-cell-restricted NF-kappaB super-repressor (IkappaBalphaDeltaN-Tg mice), we have previously shown that T-cell-NF-kappaB is essential for the acute rejection of cardiac but not skin allografts. In this study, we investigated the mechanism by which skin grafts activate IkappaBalphaDeltaN-Tg T cells. Rejection was not due to residual T-cell-NF-kappaB activity as mice with p50/p52(-/-) T cells successfully rejected skin grafts. Rather, skin but not cardiac allografts effectively induced proliferation of graft-specific IkappaBalphaDeltaN-Tg T cells. Rejection of skin grafts by IkappaBalphaDeltaN-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 IkappaBalphaDeltaN-Tg mice. Our results suggest that LC allow NF-kappaB-impaired T cells to reach an activation threshold sufficient for transplant rejection. The combined blockade of T-cell-NF-kappaB with that of alternative pathways allowing activation of NF-kappaB-impaired T cells may be an effective strategy for tolerance induction to highly immunogenic organs.