Kinetic proofreading in T-cell receptor signal transduction.

TLDR

T‑cell receptor signaling relies on sequential tyrosine phosphorylation that introduces a temporal lag, a feature that kinetic proofreading exploits to achieve high fidelity in protein and DNA synthesis. The authors propose a kinetic‑proofreading model that enhances discrimination between foreign antigens and self‑antigens of only moderately lower affinity, and a variant incorporating aggregate formation for further specificity. The model posits that sequential phosphorylation steps, optionally followed by large‑aggregate formation, allow ligands of differing affinity to trigger qualitatively distinct signaling responses.

Abstract

Like other cell-surface receptors with intrinsic or associated protein-tyrosine kinase activity, the T-cell receptor complex undergoes a number of modifications, including tyrosine phosphorylation steps, after ligand binding but before transmitting a signal. The requirement for these modifications introduces a temporal lag between ligand binding and receptor signaling. A model for the T-cell receptor is proposed in which this feature greatly enhances the receptor's ability to discriminate between a foreign antigen and self-antigens with only moderately lower affinity. The proposed scheme is a form of kinetic proofreading, known to be essential for the fidelity of protein and DNA synthesis. A variant of this scheme is also described in which a requirement for formation of large aggregates may lead to a further enhancement of the specificity of T-cell activation. Through these mechanisms, ligands of different affinity potentially may elicit qualitatively different signals.