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

The immunodominant epitope of myelin basic protein, Ac1-9, is encephal itogenic in H-2(u) mice. We have previously demonstrated that this epi tope displays low affinity for I-A(u) and have suggested that the avid ity of T cell recognition in the thymus may be compromised, enabling a utoreactive T cells to escape self-tolerance. We have addressed this h ypothesis directly by constructing transgenic mice expressing an encep halitogenic T cell receptor(TCR), Parenteral admininstration of Ac1-9 had no discernable impact on developing thymocytes. In contrast, pepti de analogs displaying far higher affinity for I-A(u), provoked deletio n of CD4(+)CD8(+) cells and transient down-regulation of the TCR by ma ture CD4(+)CD8(-) thymocytes. The use of analogs of intermediate affin ity permitted a margin of error to be defined for the induction of tol erance and confirmed that the affinity of Ac1-9 lies well below the cr itical threshold.