Indefinite tolerance to kidney allografts across a two-haplotype class I disparity can be induced in miniature swine in 100% of cases by a short course of cyclosporin A (CyA). Without CyA, all recipients reject kidney allografts within 2 wk. These animals therefore provide a unique opportunity to study the mechanisms of induction and maintenance of tolerance in a large animal model. Previous studies of cellular and humoral immunity suggested that a T cell help deficit at the time of the first exposure of the host's immune system to alloantigens was involved in tolerance induction. We have now studied the effect of exogenous T cell help in the form of an IL-2 infusion during both the induction and maintenance phases of tolerance. Lymphoid infiltrates were seen in class I mismatched renal allografts by day 8 in all animals whether treated with CyA or not. Administration of i.v. IL-2 on postoperative days 8, 9, and 10 to animals receiving the full CyA tolerizing regimen led to acute rejection in four of four animals. These rejecting animals showed induction of IL-2R expression on graft infiltrating cells in the kidney, suggesting that the infiltrates present before IL-2 administration were capable of causing rejection once T cell help was provided. Treatment with IL-2 did not abrogate long-term tolerance. Thus, limitation of T cell help at the time of first exposure to Ag in this model appears to be required to prevent rejection during the time required for active tolerance to develop. Once established, this tolerance does not appear to require continuous limitation of T cell help to be maintained, suggesting loss, inactivation, or suppression of the cells capable of causing rejection.