Ta1 (CDw26) is a 105-kDa glycoprotein of unknown function whose expression on human T lymphocytes is strongly correlated with activation and proliferation. The subset of peripheral blood T cells expressing Ta1 includes the principal responsive population to proliferative stimulation by recall antigens as well as monoclonal antibodies directed to the CD3/T cell receptor complex and the CD2 (T11) molecule. We now show that the Ta1 molecule is itself an alternate mediator of human T lymphocyte activation. T cell clones were induced to proliferate and exert their cytolytic effector function by anti-Ta1 monoclonal antibodies in the presence of Fc-receptor-positive accessory or target cells. Resting T cells from peripheral blood were also activated to proliferate by anti-Ta1, but only if both Fc-receptor-positive accessory cells and exogenous IL-2 were present. Anti-Ta1 antibodies induced increased expression of IL-2 receptors on purified T cells under these conditions. Activation via Ta1 was shown to be functionally interconnected to CD3/T cell receptor activation mechanisms, because modulation of the CD3/T cell receptor complex inhibited anti-Ta1-mediated cytolysis without affecting Ta1 surface expression. While demonstrating that the CDw26 antigen-mediated pathway of activation is not dependent on one unique epitope, our results suggest that the Ta1 glycoprotein can mediate T cell activation directly, suggesting that it may be associated with an important cellular component of the human T cell regulatory network.