The production of interferon-gamma (IFN-gamma) has been limited to two specific cell types of the immune system, T cells and large granular lymphocytes. Interleukin 2 (IL 2) appears to be the primary physiologic stimulus for IFN-gamma production in vitro, but other agents, such as antigens, phorbol myristic acetate, concanavalin A, or other plant lectins, may also act as effective inducing agents for IFN-gamma production. Little is known, however, as to the role, if any, that genetic factors may play in the induction process. We now report that, on stable transfection of the genomic human IFN-gamma 8.6 Kb BamH DNA fragment into a mouse T lymphoblast cell line, both mRNA expression and synthesis of human IFN-gamma were stimulated by both the physiologic ligand IL 2 and phorbol ester. In contrast, we have been unable to induce with extracellular stimulants IFN-gamma production or cytoplasmic mRNA after introduction of this gene into NIH 3T3 fibroblasts, thus suggesting that the extracellular regulation of the expression of IFN-gamma may be controlled by a developmental mechanism(s) intrinsic for cells of lymphoid lineage.