Tolerance induction as a multi‐step process

Abstract

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 K^b were deleted in mice carrying K^b but not in mice expressing the mutant K^b-molecule K^bm1 [TCR (H-2^{bm1 × k}) mice]. These T cells were tolerant in vivo but could be activated in vitro by the K^b antigen. This in vitro reactivity was abolished after the tolerant T cells encountered K^b-positive cells that had been intravenously injected. Furthermore, in TCR (H-2^{bm1 × k}), mice expressing K^b only on hepatocytes, no T lymphocytes bearing the transgenic TCR could be found in the periphery, indicating that the additional contact with K^b on hepatocytes led to deletion of the tolerant T cells. These findings demonstrate that tolerance induction can be a multi-step process.