Abstract
Understanding the thymic processes that support the generation of functionally competent and self-tolerant lymphocytes requires dissection of the T-cell receptor (TCR) response to ligands of different affinities. In spatially segregated regions of the thymus, with unique expression of proteases and cytokines, TCR affinity guides a number of cell fate decisions. Yet affinity alone does not explain the selection paradox. Increasing evidence suggests that the 'altered peptide' model of the 1980s together with the affinity model might best explain how the thymus supports conventional and regulatory T-cell development. Development of new tools to study the strength of TCR signals perceived by T cells, novel regulatory T-cell transgenic mice, and tetramer enrichment strategies have provided an insight into the nature of TCR signals perceived during thymocyte development. These topics are discussed and support for the prevailing hypotheses is presented.