The production of interleukin 2 (IL-2) by phytohemagglutinin (PHA)-stimulated human leukemia T cell lines MOLT-13 and MOLT-14, the T cell receptor (TcR) gamma delta-bearing clones, was significantly increased by adding human natural interferon-gamma (IFN-gamma) to the cell cultures. In addition, the IL-2 production by PHA-stimulated MOLT-13 and MOLT-14 cells was also augmented by human natural tumor necrosis factor-alpha (TNF-alpha) in a dose-dependent manner but was inhibited by IFN-alpha even at low concentrations (10 IU/ml). This pattern of reactivity is different from the responsiveness of the MOLT-16 cells, a TcR alpha beta-bearing cell line, which respond to IFN-alpha and TNF-alpha, but not to IFN-gamma, by augmentation of IL-2 production. These results suggest that (1) the addition of IFN-gamma has a direct effect on PHA-stimulated MOLT-13 and MOLT-14, resulting in an augmentation of IL-2 production; (2) phenotypically different T cell lines vary in their susceptibility to IFN-alpha and IFN-gamma regulation; and (3) the augmentation of IL-2 production by TNF-alpha appears to have no correlation with phenotypically different T cell clones.