The T-cell receptor (TCR) undergoes a series of modifications, including tyrosine phosphorylation, after ligand binding but before transmitting a signal. These modifications introduce a temporal lag between ligand binding and receptor signaling, enhancing the TCR's ability to discriminate between foreign and self-antigens. This process is known as kinetic proofreading, a mechanism essential for the fidelity of protein and DNA synthesis. A variant of this scheme involves the formation of large aggregates, further enhancing T-cell activation specificity. Ligands of different affinities may elicit qualitatively different signals through these mechanisms. T cells are sensitive to antigens present in very low abundance on antigen-presenting cells (APCs). Experimental data show that as few as 0.03% of the MHC molecules on an APC are sufficient for a T-cell response. The TCR must also have some affinity for self-peptide-MHCs for thymic maturation. However, the short length of the peptide bound by MHC may not be sufficient to cause dramatic differences in affinity between foreign and self-antigens. This raises the question of how T cells achieve both high sensitivity and high selectivity for antigen recognition. The model proposed here is based on kinetic proofreading, which posits that the mechanistic complexity of processes like DNA replication and protein synthesis, which may seem unnecessary, is essential for their accuracy. In this model, multiple independent substrate-recognition events enhance fidelity beyond what would result from small differences in binding energy. Incorrect substrates use nonproductive, energy-consuming pathways, leading to a delay between substrate binding and the enzymatic reaction. This delay allows only relatively stable complexes to be productive. The model suggests that the TCR undergoes a series of intermediate steps, including tyrosine phosphorylation, before generating an active complex. These steps involve the sequential recruitment of proteins and the formation of a large signal transduction complex. The dissociation of the complex leads to the reversal of modifications, resulting in a cycle of association and dissociation that wastes metabolic energy. The rate of dissociation of nonspecific complexes is sufficiently high that dissociation almost always occurs before activation and signal generation. The model predicts that a small difference in dissociation rates between specific and nonspecific ligands can lead to a large difference in signal generation. This is illustrated by the calculation that a 10-fold difference in affinity results in a 10,000-fold difference in response. The model also suggests that the stability of the active complex is crucial for maintaining specificity. The existence of partial agonist activity in mature T cells implies that certain responses do not require a completely activated complex. Thymocytes may require such partial responses for survival but die if significant numbers of TCR molecules are fully activated. The model may be relevant to other situations where fine discrimination between self and nonself is required, such as by B cells, natural killer cells, and phagocytes. TheThe T-cell receptor (TCR) undergoes a series of modifications, including tyrosine phosphorylation, after ligand binding but before transmitting a signal. These modifications introduce a temporal lag between ligand binding and receptor signaling, enhancing the TCR's ability to discriminate between foreign and self-antigens. This process is known as kinetic proofreading, a mechanism essential for the fidelity of protein and DNA synthesis. A variant of this scheme involves the formation of large aggregates, further enhancing T-cell activation specificity. Ligands of different affinities may elicit qualitatively different signals through these mechanisms. T cells are sensitive to antigens present in very low abundance on antigen-presenting cells (APCs). Experimental data show that as few as 0.03% of the MHC molecules on an APC are sufficient for a T-cell response. The TCR must also have some affinity for self-peptide-MHCs for thymic maturation. However, the short length of the peptide bound by MHC may not be sufficient to cause dramatic differences in affinity between foreign and self-antigens. This raises the question of how T cells achieve both high sensitivity and high selectivity for antigen recognition. The model proposed here is based on kinetic proofreading, which posits that the mechanistic complexity of processes like DNA replication and protein synthesis, which may seem unnecessary, is essential for their accuracy. In this model, multiple independent substrate-recognition events enhance fidelity beyond what would result from small differences in binding energy. Incorrect substrates use nonproductive, energy-consuming pathways, leading to a delay between substrate binding and the enzymatic reaction. This delay allows only relatively stable complexes to be productive. The model suggests that the TCR undergoes a series of intermediate steps, including tyrosine phosphorylation, before generating an active complex. These steps involve the sequential recruitment of proteins and the formation of a large signal transduction complex. The dissociation of the complex leads to the reversal of modifications, resulting in a cycle of association and dissociation that wastes metabolic energy. The rate of dissociation of nonspecific complexes is sufficiently high that dissociation almost always occurs before activation and signal generation. The model predicts that a small difference in dissociation rates between specific and nonspecific ligands can lead to a large difference in signal generation. This is illustrated by the calculation that a 10-fold difference in affinity results in a 10,000-fold difference in response. The model also suggests that the stability of the active complex is crucial for maintaining specificity. The existence of partial agonist activity in mature T cells implies that certain responses do not require a completely activated complex. Thymocytes may require such partial responses for survival but die if significant numbers of TCR molecules are fully activated. The model may be relevant to other situations where fine discrimination between self and nonself is required, such as by B cells, natural killer cells, and phagocytes. The