Unresponsiveness of mature T cells to the same self-peptide/self-MHC molecule complexes with which thymocytes have reacted during positive selection results from an increase of activation thresholds during maturation. The molecular events accounting for this increase are still unknown. In mature cells, a strong correlation between the extent of TCR down-modulation and T cell responses has been demonstrated. Exploiting this relationship, we show that the efficiency with which the TCR mediates full signaling is developmentally regulated. It decreases with thymic maturation and then increases with differentiation of naive T cells into memory lymphocytes. This analysis based on TCR modulation revealed an unexpected characteristic of the T cell receptor: its ability to signal fully is regulated inversely by its level of expression. This latter relationship may apply to other receptors both within and outside the immune system.