The property of 109 CD4+ T cell clones (TCC) to induce IgE synthesis in vitro in human B cells was compared with their ability to produce IL-2, IL-4, and IFN-gamma in their supernatants (SUP) after 24-h stimulation with PHA. A significant positive correlation was found between the property of TCC to induce or enhance spontaneous IgE synthesis and their ability to release IL-4. In contrast, there was an inverse relationship between the IgE helper activity of TCC and their ability to release IFN-gamma, whereas no statistical correlation between the property to induce IgE synthesis and to produce IL-2 was observed. The ability of PHA-SUP from 71 CD4+ TCC to induce IgE synthesis in B cells was also investigated. Twenty-nine SUP (all derived from TCC active on IgE synthesis) induced production of substantial amounts of IgE in target B cells. There was a correlation between the amount of IgE synthesized by B cells in response to these SUP and their IL-4 content. An even higher correlation was found between the IgE synthesis induced by these SUP and the ratio between the amount of IL-4 and IFN-gamma present in the same SUP. Like IL-4-containing SUP, rIL-4 also showed the ability to induce IgE production in B cells from both atopic and nonatopic donors. The addition to B cell cultures of anti-IL-4 antibody virtually abolished not only the IgE synthesis induced by rIL-4, but also that stimulated by TCC and their SUP. In contrast, the IgG synthesis induced by TCC SUP was not or only slightly inhibited by the anti-IL-4 antibody. These data indicate that IL-4 is an essential mediator for the IgE synthesis induced in vitro by human TCC and their SUP in the absence of a polyclonal activator, whereas IFN-gamma seems to exert a negative regulatory effect on the production of IgE.