SUMMARYIn this study the role of the thymus as a possible site of induction and maintenance of specific immune tolerance to cellular alloantigens was investigated. It has been shown that sublethally irradiated mice can be made tolerant by an injection of H-3 incompatible spleen cells into or outside the thymus. When the inoculum was given extrathymically, dividing donor cells were found to penetrate into the thymus if the recipient was either newborn or sublethally irradiated when adult. A direct inoculation into the thymus would thus not be required for an intrathymic action of antigen in tolerance induction in the case of those cellular antigens which seem to possess a natural vehicle.In a second approach to the same problem, strain A mice were lethally irradiated and induced to recover by infusion of syngeneic fetal liver cells. The immature lymphoid cells from the curative inoculum are thymus-dependent and tolerance-responsive. Use has been made of this situation by replacing the recipients' thymus by a syngeneic, but presumably CBA cell-containing, thymus (from donors tolerant to CBA antigens) or by a semiallogeneic thymus (from (A × CBA) F1hybrids). In both cases, the implanted thymus was the only source of CBA antigens for the induction of tolerance in the fetal cells. In the former case, where the “tolerant” thymuses were implanted subcutnneously to the radiation chimeras, only prolonged survival of CBA skin grafts resulted. The implantation of F1hybrid thymuses under the kidney capsule resulted in a high degree of permanent tolerance (i.e., lasting for more than 150 days). Transfer of hybrid lymph nodes to nonthymectomized but splenectomized chimeras resulted in only temporary tolerance while the effect of hybrid spleen was comparable to that of the thymus. A possible explanation of these findings based on a thymus-mediated mechanism of tolerance to cellular alloantigens is suggested.