T-cell-receptor affinity and thymocyte positive selection

Abstract

Development of thymocytes involves two distinct outcomes resulting from superficially similar events. Recognition by thymocytes of major histocompatibility complex (MHC) proteins plus peptides leads to their rescue from apoptosis (positive selection), and recognition of antigenic peptide induces cell death (negative selection). Antigen analogues, and sometimes low concentrations of antigenic peptide, induce positive selection; such analogues are often antagonists of mature T-cell clones. Various models seek to explain how recognition of different peptide/MHC complexes leads to such different outcomes: quantitative models relate response to the affinity, avidity or kinetics of T-cell-antigen receptor (TCR) binding, whereas qualitative models require conformational or spatial changes in the TCR or associated molecules to modulate signal transduction. We have used surface plasmon resonance to measure the kinetics of TCR interactions with positively and negatively selecting ligands to distinguish between these models, and find that affinity correlates to the outcome of selection. A 'window' of affinity resulting in positive selection extends over a 1-log range starting threefold below the affinity for negative selection.