Tolerance induction in mature T lymphocytes.

T lymphocytes with self-destructive capacity are often found in healthy individuals, indicating efficient control mechanisms that prevent autoimmunity. Recently, we were able to demonstrate the existence of peripheral tolerance in double-transgenic mice expressing the foreign histocompatibility antigen H-2Kb exclusively outside the thymus and a T cell receptor (Des.TCR) directed against the Kb molecule. In mice expressing Kb only on keratinocytes anti-Kb T cells were still present but failed to reject Kb-positive tissue grafts. This observation would imply a continuous migration of naïve T cells exported from the thymus into non-lymphoid tissues where these fresh thymic emigrants would need to be tolerized. However, this is in contrast to the view that migration to peripheral tissues is restricted to activated T cells. To investigate whether there is a continuous process of tolerization of naïve T cells in adult DES.TCR x 2.4Ker-Kb mice, 2.4Ker-Kb mice were crossed with Rag-2-deficient mice and reconstituted with bone marrow cells of Des.TCR transgenic mice (Des.TCR x 2.4Ker-Kb.Rag-2-). Tolerance was not observed in these chimeric mice. We conclude from these results that in contrast to the neonate the adult physiological environment does not allow tolerance induction to antigens expressed on keratinocytes in T cells newly exported from the thymus. Furthermore, we have to postulate regulatory events responsible for the maintenance of peripheral tolerance in the adult Des.TCR x 2.4Ker-Kb animals.

Tolerance induction as a multi-step process.

Tolerant T cells are characterized by their partial or full resistance to activation by antigen. We investigated whether tolerant T cells were still receptive to further tolerogenic signals. T cells expressing a transgenic T cell receptor (TCR) specific for the major histocompatibility complex (MHC) class I molecule Kb were deleted in mice carrying Kb but not in mice expressing the mutant Kb-molecule Kbm1 [TCR (H-2bm1 x k) mice]. These T cells were tolerant in vivo but could be activated in vitro by the Kb antigen. This in vitro reactivity was abolished after the tolerant T cells encountered Kb-positive cells that had been intravenously injected. Furthermore, in TCR (H-2bm1 x k) mice expressing Kb only on hepatocytes, no T lymphocytes bearing the transgenic TCR could be found in the periphery, indicating that the additional contact with Kb on hepatocytes led to deletion of the tolerant T cells. These findings demonstrate that tolerance induction can be a multi-step process.