A transgenic window on peripheral T cell tolerance.

There is convincing evidence for the imposition of self-tolerance by means of the clonal deletion of self-reactive T cells 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 'non-self' gene, H-2Kb, to the insulin-producing beta cells of the pancreas in mice. These 'RIP-Kb' transgenic mice were specifically tolerant of H-2Kb-bearing skin grafts. To test the fate of potentially reactive H-2Kb-specific T cells in these tolerant mice, the RIP-Kb mice were mated to a second series of transgenic mice with rearranged T cell receptor (TCR) genes encoding an H-2Kb-specific TCR to produce 'double transgenic' offspring. The TCR was detectable by a clonotype-specific antibody. Although there was some evidence of intrathymic deletion of those T cells that expressed the highest density of the H-2Kb-specific TCR, lower density cells were present in the periphery. These may have been either indifferent to the H-2Kb molecule expressed on the beta cells or functionally silenced by it. Further experiments are planned to determine which of these two situations exists.