The response of highly enriched populations of human T8+ lymphocytes to the oxidative mitogenic enzymes neuraminidase (NA) and galactose oxidase (GO) was enhanced by NAGO-primed T4+ lymphocytes. No similar enhancement occurred when the cells were primed with phytohemagglutinin (PHA). In the absence of subclass contamination (1%), the T8+ and T4+ cells responded equally to NAGO by the criterion of DNA replication. The addition of a small number, 2-10%, of NAGO-T4+ cells to the NAGO-T8+ cells enhanced DNA synthesis by as much as 8.5-fold. Augmentation of the cellular response did not occur unless the T4+ cells were activated by NAGO. The converse situation, 2-10% of NAGO-T8+ cells in a primarily NAGO-T4+ cell population, did not increase the DNA synthetic response of the NAGO-T4+ cells. The NAGO-T4+ cells did not augment the early event of increased phosphatidylinositol metabolism or the midcycle event of induction of receptors for interleukin 2 (IL2) and transferrin. The NAGO-T4+ cells therefore increased the probability that fully activated T8+ lymphocytes crossed the G1/S boundary. The basis for this effect was not an enhanced responsiveness of the NAGO-T8+ cells to IL2 or to other soluble growth mediators in medium conditioned by NAGO-activated lymphocytes. The results of this investigation thus implicate a control point in the NAGO-T8+ lymphocyte cell cycle that is positively modulated by the NAGO-T4+ cells themselves or by a product of their activation.