Specificity and flexibility in thymic selection.

During positive selection, developing thymocytes are rescued from programmed cell death by T-cell receptor (TCR)-mediated recognition of major histocompatibility complex (MHC) molecules. MHC-bound peptides contribute to this process. Recently we identified individual MHC-binding peptides which can induce positive selection of a single TCR. Here we examine peptide fine specificity in positive selection. These data suggest that a direct TCR-peptide interaction occurs during this event, and strengthens the correlation between selecting peptides and TCR antagonists. Certain positively selecting peptides are weakly antigenic. We demonstrate that thymocytes 'educated' on such a peptide are specifically non-responsive to it and have decreased CD8 expression levels. Similar reduction of CD8 expression on mature T cells converts a TCR agonist into a TCR antagonist. These data indicate that thymocytes may maintain self-tolerance towards a positively selecting ligand by regulating co-receptor expression.