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A transgenic window on peripheral T cell tolerance
1Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
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.
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.