title: Low avidity recognition of self-antigen by T cells permits escape from central tolerance.
abstract: The immunodominant epitope of myelin basic protein, Ac1-9, is encephalitogenic in H-2u mice. We have previously demonstrated that this epitope displays low affinity for I-Au and have suggested that the avidity of T cell recognition in the thymus may be compromised, enabling autoreactive T cells to escape self-tolerance. We have addressed this hypothesis directly by constructing transgenic mice expressing an encephalitogenic T cell receptor (TCR). Parenteral administration of Ac1-9 had no discernable impact on developing thymocytes. In contrast, peptide analogs displaying far higher affinity for I-Au, provoked deletion of CD4+ CD8+ cells and transient down-regulation of the TCR by mature CD4+ CD8- thymocytes. The use of analogs of intermediate affinity permitted a margin of error to be defined for the induction of tolerance and confirmed that the affinity of Ac1-9 lies well below the critical threshold.
authors.affiliation: Cambridge University Department of Pathology, England.
authors.forename: G Y
authors.initials: GY
authors.lastname: Liu
authors.forename: P J
authors.initials: PJ
authors.lastname: Fairchild
authors.forename: R M
authors.initials: RM
authors.lastname: Smith
authors.forename: J R
authors.initials: JR
authors.lastname: Prowle
authors.forename: D
authors.initials: D
authors.lastname: Kioussis
authors.forename: D C
authors.initials: DC
authors.lastname: Wraith
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell