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Deletion of high-avidity T cells by thymic epithelium.
Hoffmann MW; Heath WR; Ruschmeyer D; Miller JF; Klinik fur Abdominal-
January 30, 1996
Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9851-5. Unique Identifier :

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-2Kb (Kb), 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 Kb-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 Kb-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 Kb. 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 Kb skin graft was not broken. Finally, direct evidence could be obtained for the avidity model of thymic epithelium-induced negative selection, using Kb-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 Kb. 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.

Animal *Clonal Deletion CD8-Positive T-Lymphocytes/IMMUNOLOGY Epithelium/IMMUNOLOGY Graft Rejection Graft Survival H-2 Antigens/IMMUNOLOGY Mice Mice, Inbred BALB C Mice, Inbred CBA Mice, Inbred C57BL Mice, Nude Mice, Transgenic Models, Immunological Receptors, Antigen, T-Cell Skin Transplantation/IMMUNOLOGY Spleen/TRANSPLANTATION Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. T-Lymphocytes/*IMMUNOLOGY T-Lymphocytes, Cytotoxic/IMMUNOLOGY T-Lymphocytes, Helper-Inducer/IMMUNOLOGY Thymus Gland/*IMMUNOLOGY Tissue Transplantation JOURNAL ARTICLE

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