The survival and proliferation of CTL during the effector phase of the immune response is critical for the elimination of infectious agents and tumor cells. We report here that in an in vitro model system, the expansion and cytolytic function of tumor-reactive human CTL can be enhanced by CD4(+) helper T lymphocytes through costimulatory signals that are mediated by cell surface molecules. The results presented here suggest that costimulatory receptors on CTL such as CD27, CD134 (4-1BB), and MHC class II are capable of directly interacting with the corresponding ligands on T-helper lymphocytes resulting in enhanced proliferation and survival of the CTL during the effector phase of antitumor immune responses. These findings underline the importance of antigen-specific helper T lymphocytes for the regulation and maintenance of CTL immunity, and have implications for the design of therapeutic vaccines for cancer.