Early intracellular signals in response to anti-Leu4 in T cells were studied. There are two groups whose T cells, in the presence of accessory cells, proliferate (responders) or not (nonresponders) in response to anti-CD3 antibodies of the subclass IgG1, as is the case with anti-Leu4. Approximately 30% of Protein Kinase C (PKC) in the cytosol fraction disappeared temporarily, thereby indicating PKC activation, in response to immobilized anti-Leu4. PKC activation in purified T cells was detected both in responders and in nonresponders. The stimulation by anti-Leu4 crosslinked with goat anti-mouse IgG led to an increase in intracellular free calcium concentration [Ca++]i) in the T cells, and this increase was identical in responders and nonresponders. Although minimal Interleukin 2 (IL-2) receptor expression was apparent, T cells even from responders failed to proliferate in response to anti-Leu4, in the absence of accessory cells. Thus, in T cells from responders or nonresponders, anti-Leu4 stimulation induces early intracellular signal transduction and IL-2 receptor expression, but without accessory cells, proliferation does not occur.