Cytotoxic T lymphocytes are major effector cells in response to viral infections and in allograft rejection and are implicated in many other immunological reactions. Efficient induction of cytotoxic activity in these cells in many but not all cases depends upon helper T and antigen-presenting cells so that at least three different cell types have to work together. Here we present an in vitro model for the helper T cell-dependent induction of cytotoxic T lymphocytes which allows the investigation of the collaboration of helper and cytotoxic T cells. First results demonstrate that linkage of helper and killer epitopes on the surface of one antigen-presenting cell is a prerequisite for productive interaction between the two T cells that results in induction of cytolytic activity. T helper 1 and T helper 2 cells are equally efficient. The crucial roles of interleukin-2 and interferon-gamma in this process were confirmed. Activated CD4 cells can influence cytotoxic T lymphocytes in such a way that they produce interferon-gamma independent from recognition of cognate peptide. The possibility of direct T-T contacts mediated by adhesion molecules that promote collaboration of the two cells is discussed.