DELETION OF HIGH-AVIDITY T-CELLS BY THYMIC EPITHELIUM

Tolerance induction by thymic epithelium induces a state of so-called ''split tolerance,'' characterized in vivo by tolerance and in vitro by reactivity to a given thymically expressed antigen. Using a model major histocompatibility complex class I antigen, H-2K(b) (K-b), three mechanisms of thymic epithelium-induced tolerance were tested: induction of tolerance of tissue-specific antigens exclusively, selective inactivation of T helper cell-independent cytotoxic T lymphocytes, and deletion of high-avidity T cells, To this end, thymic anlagen from K-b-transgenic embryonic day 10 mouse embryos, taken before colonization by cells of hemopoietic origin, were grafted to nude mice. Tolerance by thymic epithelium was not tissue-specific, since K-b-bearing skin and spleen grafts were maintained indefinitely, Only strong priming in vivo could partially overcome the tolerant state and induce rejection of some skin grafts overexpressing transgenic K-b, Furthermore, the hypothesis that thymic epithelium selectively inactivates those T cells that reject skin grafts in a T helper-independent fashion could not be supported, Thus, when T-cell help was provided by a second skin graft bearing an additional major histocompatibility complex class II disparity, tolerance to the K-b Skin graft was not broken, Finally, direct evidence could be obtained for the avidity model of thymic epithelium-induced negative selection, using K-b-specific T-cell receptor (TCR) transgenic mice, Thymic epithelium-grafted TCR transgenic mice showed a selective deletion of those CD8(+) T cells with the highest density of the clonotypic TCR, These cells presumably represent the T cells with the highest avidity for K-b. We conclude that split tolerance induced by thymic epithelium was mediated by the deletion of those CD8(+) T lymphocytes that have the highest avidity for antigen.