Interactions mediated by TCRs expressed on different T cell subsets may play a role in immunoregulation. To investigate this idea, we studied the regulation of superantigen-induced TCR Vp-restricted responses. We asked whether the in vivo regulation of CD4(+) V beta 8(+) T cells following SEB injection is controlled by CD8(+) T cells. We found that in mice deficient in CD8(+) T cells, the down-regulation of CD4(+) V beta 8(+) T cells below baseline is not observed. Moreover, following SEB administration, CD8(+) T cells emerge that preferentially kill subpopulations of activated CD4(+) V beta 8(+) but not CD4(+) V beta 8(+) T cells in vitro. This TCR V beta-specific cytotoxicity is dependent on beta 2-microglobulin and is inhibited by antisera specific for Qa-l but not by antibody to MHC class la. These data suggest the idea that the specificity of immune regulation may involve CD8(+) T cell recognition of TCR V beta determinants and Qa-1 molecules expressed on CD4(+) T cells.