       Document 0198
 DOCN  M9610198
 TI    Deletion of high-avidity T cells by thymic epithelium.
 DT    9601
 AU    Hoffmann MW; Heath WR; Ruschmeyer D; Miller JF; Klinik fur Abdominal-
       und Transplantationschirurgie,; Medizinische Hochschule Hannover,
       Germany.
 SO    Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9851-5. Unique Identifier :
       AIDSLINE MED/96003877
 AB    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.
 DE    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

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

