LOW AVIDITY RECOGNITION OF SELF-ANTIGEN BY T-CELLS PERMITS ESCAPE FROM CENTRAL TOLERANCE

The immunodominant epitope of myelin basic protein, Ac1-9, is encephalitogenic in H-2(u) mice. We have previously demonstrated that this epitope displays low affinity for I-A(u) 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 admininstration of Ac1-9 had no discernable impact on developing thymocytes. In contrast, peptide analogs displaying far higher affinity for I-A(u), 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.