T cells can be divided into unprimed virgin (T°) and primed memory (T') subpopulations by their expression of different isoforms of the leukocyte common antigen. We have separated the CD4 + T cells into T° and T' subpopulations and examined their capacity to respond to activation signals via the CD2 receptor molecule. On stimulation with a mitogenic combination of anti-CD2 antibodies, the T' population was inducd to express IL-2 receptor, increased levels of the 4F2 antigen and to proliferate, whereas the response of the T° populations was reflected solely by a minimal increase in the 4F2 antigen. The addition of IL-2 or monocytes to T° cells stimulated with anti-CD2 antibodies did not enhance their expression of the IL-2 receptor or proliferation. However, T° cells stimulated with the tried of anti-CD2 antibodies, monocytes, and IL-2 responded with high levels of IL-2 receptor expression and proliferation. The T° subpopulation could also be induced to respond when cultured with anti-CD2 antibodies and phorbol myristate acetate. The results suggest that in order to respond to stimulation via the CD2 molecule, virgin T helper cells require additional signals that can be jointly provided by monocytes and IL-2. In contrast, memory T helper cells can be activated via CD2 signal transduction alone.