Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen

Self-reactive T lymphocytes escaping thymic tolerance induction can be rendered non-responsive by contact with antigens in the periphery. In order to determine the parameters controlling peripheral tolerance induction we followed the fate of one well-defined self-reactive T cell population in three different mice expressing the self antigen in various nonlymphoid tissues outside the thymus. This was achieved by crossing anti-Kb T cell receptor (TCR) transgenic mice with transgenic animals expressing the Kb antigen exclusively on hepatocytes or keratinocytes or neuroectodermal cells. Due to this differential expression clonotype+, anti-Kb reactive T cells were found to exist at three different levels of tolerance. These levels were distinct with regard to downregulation of TCR and CD8 molecules, and the requirements for reexpression of TCR in vitro. This differential induction of peripheral tolerance suggest that some tissues are more likely to be affected in autoimmune diseases than others.