All or none peripheral tolerance induction in H-Y antigen-specific TCR transgenic mice.

In in vivo tolerance induction, the dose of tolerogen injected is generally linearly correlated to the length of tolerance induced. Small, medium and large doses are related to no, partial and long-term tolerance, respectively. However, even with injection of substantially large doses of tolerogen, the length of tolerance induced varies over a wide range. Most of the recipients can still reject donor grafts. In this study, it is shown that the linear dose-response can be altered into an all or nothing response in a H-Y antigen-specific TCR transgenic (Tg) mouse model. In thymectomized female Tg mice, injection of 3, 30 and 100 x 10(6) male spleen cells was correlated to no, partial and massive deletion of Tg (alpha T beta T) CD8 cells, respectively. When the thymectomized Tg mice were injected with 9 x 10(6) T cell-enriched (T+) male cells, one half of the recipients showed no deletion of alpha T beta T cells, and in the other half massive deletion occurred. In complete correlation with deletion, all male skin grafts were rejected in the undeleted group as PBS-injected controls, whereas with massive deletion they were indefinitely tolerized. Thus, partial deletion and partial tolerance can be avoided. Injection of 18 x 10(6) male T+ cells induced long-term tolerance in all the recipients. The all or none T cell deletion and long-term tolerance induction has not only significant implications in understanding the mechanism of peripheral tolerance induction, but also in tolerance induction in transplantation, gene therapy and the prevention and treatment of autoimmune diseases.