Cloned, Lyt-1+,2-, antigen-specific, Ia-restricted T cell lines can inhibit the growth of Ia-bearing B lymphoma cells in the presence of specific antigen. This effect is due to cytolysis of the B lymphoma cells in an antigen-specific, Ia-restricted manner by the cloned T cell lines. These cloned T cell lines can also kill lipopolysaccharide-activated normal B cells, while they activate resting B cells to divide and secrete immunoglobulin and are thus helper T cells as well as cytolytic T cells. The mechanism of cytolysis was examined in detail. Killing was mediated by a nonspecific mechanism after specific stimulation of the T cells with antigen presented in the context of the appropriate Ia glycoprotein complex, possibly implying a role for a soluble mediator. This simple system involving two clonal populations allows a detailed analysis of T-B interactions. Our studies are consistent with the view that both cognate and noncognate interactions of Ia-restricted T cells with B cells are mediated by nonspecific factors. Thus, the difference between interactions that appear to be cognate and those that appear to be noncognate may be quantitative rather than qualitative. That two cloned populations of cells can show either pattern of interaction depending on T-B ratio provides strong support for this view. Finally, that cloned helper T cells can kill activated B cells in an antigen-specific fashion may provide a new mechanism of immune regulation that would be especially important in responses to self antigens in vivo.