There is now convincing evidence for the imposition of self-tolerance by means of the clonal deletion of self-reactive T cells operating within the thymus. Since not all self components may be encountered there, the question must be asked whether tolerance can occur post-thymically. To test this, we have used transgenic technology to direct expression of a known 'non-self' gene, H-2Kb, to the insulin producing beta cells of the pancreas of mice. H-2Kb-bearing skin, but not skin from other mouse strains, failed to be rejected by the 'RIP-Kb' transgenic mice indicating specific tolerance. Following in vitro stimulation, their spleen cells could not kill H-2Kb-bearing targets, but could respond to third party targets. Their reactivity to H-2Kb was restored by providing them with IL-2. Two hypotheses could account for the above: tolerance results either from the deletion or functional silencing of high affinity effector cytotoxic cells or of regulatory, IL-2-producing helper T cells. Since it is difficult to distinguish between these, we have produced a second series of transgenic mice with rearranged T cell receptor (TCR) genes encoding an anti-H-2Kb TCR, and obtained 'double transgenic' offspring by mating these mice with RIP-Kb mice. The TCR utilized the V beta 11 segment which can be detected by a monoclonal antibody. Although the double transgenic mice were tolerant of H-2Kb, there was no evidence of deletion of anti-H-2Kb T cells. It seems, therefore, that a non-deletional mechanism operates to induce post-thymic tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)