The mechanism of T cell activation has been studied employing both cloned T cell populations and naive heterogeneous T cell populations. Comparison has been made of T cell stimulation by antibodies directed to allotypic determinants on the T cell receptor, T cell activation by specific antigen, and T cell activation by non-receptor-mediated signaling. It has been demonstrated that both cloned and naive T cells can be triggered by the monoclonal antibody F23.1, directed toward determinants on the T cell receptor. Naive Lyt2+ T cells were activated to proliferate in the presence of soluble F23.1, IL-2, and accessory cells. Under the same conditions, L3T4+ naive T cells were unresponsive. These findings thus demonstrated a difference in the activation requirements of T cell subpopulations triggered through T cell receptor determinants. Specific "targeting" of the T cell receptor to accessory cell structures by heteroaggregates of F23.1 coupled to monoclonal anti-Ia antibody were, in contrast, capable of activating both Lyt2+ and L3T4+ T cell subpopulations. The nature of activation signals provided under these diverse conditions is currently under study.