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 b y reactivity to a given thymically expressed antigen. Using a model ma jor histocompatibility complex class I antigen, H-2K(b) (K-b), three m echanisms of thymic epithelium-induced tolerance were tested: inductio n of tolerance of tissue-specific antigens exclusively, selective inac tivation of T helper cell-independent cytotoxic T lymphocytes, and del etion of high-avidity T cells, To this end, thymic anlagen from K-b-tr ansgenic embryonic day 10 mouse embryos, taken before colonization by cells of hemopoietic origin, were grafted to nude mice. Tolerance by t hymic epithelium was not tissue-specific, since K-b-bearing skin and s pleen grafts were maintained indefinitely, Only strong priming in vivo could partially overcome the tolerant state and induce rejection of s ome skin grafts overexpressing transgenic K-b, Furthermore, the hypoth esis that thymic epithelium selectively inactivates those T cells that reject skin grafts in a T helper-independent fashion could not be sup ported, Thus, when T-cell help was provided by a second skin graft bea ring an additional major histocompatibility complex class II disparity , tolerance to the K-b Skin graft was not broken, Finally, direct evid ence could be obtained for the avidity model of thymic epithelium-indu ced negative selection, using K-b-specific T-cell receptor (TCR) trans genic mice, Thymic epithelium-grafted TCR transgenic mice showed a sel ective deletion of those CD8(+) T cells with the highest density of th e clonotypic TCR, These cells presumably represent the T cells with th e highest avidity for K-b. We conclude that split tolerance induced by thymic epithelium was mediated by the deletion of those CD8(+) T lymp hocytes that have the highest avidity for antigen.