A T cell clone as well as immediately ex vivo CD4+ lymph node T cells are shown to support the differentiation of co-cultured resting B cells in the absence of T cell-B cell contact. Antibodies specific for class II products of the major histocompatibility complex inhibit the transactivation of resting but not activated B cells. This differential inhibition pattern indicates that the responses obtained from resting B cell populations are not due to their contamination with B cell blasts. Further, supernatants prepared from an activated T cell clone induce resting B cell differentiation. Two lines of evidence suggest that the activity contained in these supernatants can be attributed to interleukin (IL)-5. Activity is neutralized by monoclonal anti-IL-5; and both recombinant and affinity-purified IL-5 induce the differentiation of immediately ex vivo resting and activated B cells with comparable efficiency. Taken together, these results demonstrate that contact with T cells does not provide prerequisite signals for the induction of resting B cell differentiation.