Recent studies support the possibility of an interaction between CD4/8 and the TCR complex. To determine if there is specificity in this interaction, we have studied the comodulation of CD4/8 with the CD3/TCR complex on a CD4+ CD8+ human leukemic T-cell line stimulated with staphylococcal enterotoxin A (SEA) bound to Raji cells. FACS analysis revealed that CD3 and the TCR were modulated from the surface. CD4 and not CD8 was comodulated with the T-cell receptor complex, supporting the existence of a docking site on the TCR with selectivity for CD4 or CD8 but not both. Fewer than 45 SEA molecules per presenting cell led to detectable comodulation. The ratio of %CD4/%TCR modulation varied with both time and the amount of SEA used for stimulation. ConA or PHA induced modulation of CD3 but, unlike SEA, failed to induce IL-2 secretion, suggesting multiple pathways and states of T-cell activation. Our findings also suggest that some human T leukemic lines can respond to antigen.