The regulation of the subclass of immunoglobulin secreted by B cells has been studied in vitro in polyclonal systems using mitogens, such as lipopolysaccharide (LPS), to bypass the requirement for cognate interaction between antigen-specific T and B cells. In these systems, interleukin-(IL)-4 induces the secretion of IgG₁, (ref. 1) and IgE (ref. 2); IL-5 enhances the secretion of IgA^3,4, and interferon-γ (IFN-γ) enhances the secretion of IgG_2a (ref. 5). Clones of murine T_H cells can be divided into two subsets, TH₁ and T_H2 (ref. 6). Both subsets synthesize IL-3 and granulocyte-monocyte colony-stimulating factor (GM-CSF), but only T_H1 clones produce IL-2, IFN-γ, and lymphotoxin (LT) and T_H2 clones produce IL-4 and IL-5 (ref. 7). We have examined the role of clones of antigen-specific T_H1 and T_H2 cells in the regulation of the subclasses of IgG antibody secreted by antigen-specific B cells. Our results show that both types of T_H cells induce the secretion of IgM and IgG₃, whereas clones of T_H1 and T_H2 cells specifically induce antigen-specific B cells to secrete IgG_2a and IgG₁, respectively. We also demonstrate that regulation of commitment to the secretion of a particular IgG isotype occurs in two distinct stages: cognate interaction between T and B cells and interaction between T-cell-derived lymphokines and B cells.