Professional antigen-presenting cells (APCs) are capable of transporting self-antigens from peripheral tissues to secondary lymphoid organs where they are presented to potentially autoreactive CD8(+) T cells. In the absence of an inflammatory response, this results in immune tolerance. The presence of activated, antigen-specific CD4(+) T cells converts this tolerogenic encounter into an immunogenic one by promoting extensive proliferation of CD8(+) T cells and their development into effectors. Surprisingly, activation of APCs with an agonistic antibody specific for CD40 could not substitute for CD4(+) help in this task. Anti-CD40 induced recruitment of dendritic cells expressing high levels of B7 costimulatory molecules into the lymph nodes, which in turn, greatly enhanced activation and expansion of CD8(+) T cells. However, these activated CD8(+) cells did not demonstrate effector function. We conclude that proliferative potential and gain of effector function are separable events in the differentiation program of CD8(+) T cells.