Low avidity recognition of self-antigen by T cells permits escape from central tolerance

• Published in: Immunity (Cambridge, Mass.) Mass.), 1995-10, Vol.3 (4), p.407-415
• Main Authors: Liu, G Y, Fairchild, P J, Smith, R M, Prowle, J R, Kioussis, D, Wraith, D C
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Antibody Affinity; Autoantigens - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Encephalomyelitis, Autoimmune, Experimental - immunology; Immune Tolerance; Lymphocyte Activation; Mice; Mice, Transgenic; Myelin Basic Protein - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology
• ISSN: 1074-7613
• DOI: 10.1016/1074-7613(95)90170-1

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.