Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells

Determining how receptor ligand quality and quantity together control the biologic responses of T cells is central to understanding normal and pathologic T cell immunity. Here we have carefully examined how variations in antigenic peptide structure and dose affect multiple functional responses of human T cell clones and have correlated these observations with proximal TCR signaling events induced by the same set of related ligands. As the Ag concentration increases, effector functions are elicited according to a clone-specific hierarchy. The absolute amount of each peptide required to stimulate the entire set of effector functions (potency) differs markedly among ligands for a single TCR, correlating with the efficiency of TCR down- modulation and the extent of ZAP-70 activation. However, distinct patterns of TCR ζ-chain phosphorylation were observed, with the ratios of TCRζ isoforms relating to ligand agonist potency. The appearance of partially phosphorylated TCRζ isoforms was paralleled by relative changes in certain response thresholds within the hierarchy. Thus, a combination of density, potency, and quality of signaling all contribute to the distinct effects of agonist ligands on T cell immunity.