Daudi Burkitt's lymphoma cells stimulate the proliferation of V gamma 2 V delta 2 T cells in human peripheral blood mononuclear cells (PBMC). Transfection studies have established that the gamma delta T cell receptor is sufficient for recognition of a ligand associated with Daudi cells. Since other studies have demonstrated the need for cooperation between alpha beta T cells and V gamma 2 V delta 2 T cells in the proliferative response to mycobacterial antigens, we used human, unfractionated PBMC and PBMC depleted of specific T cell subsets to determine whether the gamma delta T cell response to Daudi cells also requires cooperation between alpha beta and gamma delta T cells. In the current study, we demonstrate that depletion of CD4(+) T cells substantially reduces the overall proliferative response of PBMC to Daudi cells and subsequent gamma delta T cell expansion. IL-2 production by PBMC in response to Daudi cells was also decreased by depletion of CD4(+) T cells, but not by depletion of CD8(+) or gamma delta T cells. In the CD4(+) T-cell-depleted PBMC, proliferation in response to Daudi cells was restored by the addition of IL-2. These data stress the importance of cooperation between alpha beta and gamma delta T cells in the response to some complex antigens. (C) 1996 Academic Press, Inc.