On the issue of peptide recognition in T cell development.

CD4-CD8 double positive (DP) thymocytes undergo a differentiation process in the thymus where they are selected based on their ability to recognize peptide antigens presented on self major histocompatibility complex (MHC) molecules. The first stage of this process is positive selection, a quality-control mechanism which ensures that the T cell receptors (TCR) presented on developing thymocytes can transmit signals via peptides presented on either MHC class I (MHC1) or MHC class II (MHC2) molecules. Work over the past decade has revealed that the peptides that drive positive selection of both CD4 and CD8 lineage cells deliver only weak TCR signals. In line with these observations, specialized protein degradation machineries have been discovered in the thymic cortex that presumably generate specialized low-affinity peptide repertoires for presentation on MHC1 and MHC2 molecules. TCR signals transduced through these weak-affinity ligands in the early stages of positive selection alter the kinetics of expression of CD4 and CD8 molecules and play a crucial role in commitment of thymocytes to either the CD4 or CD8 lineages. In this work, we review the experiments that explore the peptide repertoires that are presented to developing thymocytes during positive selection, the observed signaling patterns that lead to CD4 versus CD8 lineage commitment, and speculate about how specialized organization of the signaling machinery in DP thymocytes may allow for efficient transduction of weak signals during the course of positive selection.