It is currently believed that IgE production by B cells is induced by activated CD4+ Th2-like cells that produce increased amounts of IL-4 but low levels of IFN-gamma. We found that "naive" CD4+ 45RO- T cells primed and restimulated in vitro via the TCR developed into effector cells that produced large amounts of IL-13, IL-5, and IFN-gamma, but no IL-4. Such CD4 T cells induced surface IgD+E- B cells to produce large amounts of IgE. The IgE response could be blocked completely by neutralizing anti-IL-13 Abs, whereas anti-IL-4 had no effect. Addition of exogenous IL-4 during priming of CD4 cells suppressed clonal expansion and the development of Th cells including helpers for IgE, but increased endogenous production of IL-4 and IL-5, and suppressed production of IFN-gamma. Addition of exogenous IFN-alpha, IFN-gamma, or neutralizing anti-IFN-gamma mAbs affected neither priming of CD4 T cells nor B cell help. In contrast to CD4+ 45RO- naive T cells, CD4+ 45RO+ "memory" T cells primed and restimulated in vitro secreted IL-4 in addition to IL-13, IL-5, and IFN-gamma, and the IgE response induced by such cells could be blocked only by a combination of anti-IL-4 plus anti-IL-13 Abs. Unlike CD4 cells, CD8 cells could not be primed to help IgE production. The results indicate that TCR/CD3 cross-linking on naive human CD4 T cells is sufficient to induce the development of potent IgE helper cells, which secrete large amounts of IL-13, IL-5, and IFN-gamma, but no IL-4. Such Th cells may exacerbate atopic inflammation, because all by themselves they could drive IL-13-dependent IgE production, IL-5-dependent eosinophilia, and IFN-gamma-dependent macrophage activation, but could not suppress IFN-gamma production by other T cells via IL-4.