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^1-3. MHC-bound peptides contribute to this process^4-8. Recently we identified individual MHC-binding peptides which can induce positive selection of a single TCR ⁹. 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^9,10. Certain positively selecting peptides are weakly antigenic⁹. We demonstrate that thymocytes 'educated' on such a peptide are specifically non-responsive to it and have decreased CDS expression levels. Similar reduction of CDS 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.