In a recent study, a superantigen mutated in the TCR binding site (staphylococcal enterotoxin B (SEB)Delta 61Y) was described, which behaved as a partial agonist for a V beta 17-expressing T-cell clone. Evidence is now presented to demonstrate that there is distinct heterogeneity in the response of primary T cells to this protein. Some V beta 17 T cells responded to SEB Delta 61Y by modulating surface receptor expression consistent with activation, and by proliferating. Other V beta 17 T cells did not proliferate, nor did they display a receptor expression phenotype consistent with activation. However, when repeatedly exposed to the altered superantigen, some of these non-responders entered cell cycle. This pattern of responses was not recapitulated by providing additional costimulation via CD28, although such treatment did induce some of the 'unresponsive' V beta 17 T cells to upregulate the IL-2 receptor, indicative of partial activation. It was also found that the heterogeneous pattern could be replicated using very low doses of native SEB. The data are discussed in the context of models of T-cell activation in which differences in TCR ligand affinity and dose determine qualitatively different response phenotypes.