TGF-β has marked inhibitory effects on the immune system but also serves as a costimulatory factor in the development of T cells with down-regulatory activities. This cytokine is secreted as a latent complex and converted extracellularly to its active form. We have recently learned that anti-CD2 is a potent inducer of lymphocyte-derived TGF-β and that NK cells are the predominant source. The objective of this study was to compare levels of constitutive, anti-CD2-induced and cytokine-regulated TGF-β produced by blood lymphocytes from patients with systemic lupus erythematosus (SLE) in comparison with healthy controls. Using a highly sensitive and specific bioassay to assess TGF-β, we report that unstimulated PBL from SLE patients, especially the NK cell subset, produced decreased levels of active TGF-β. In response to anti-CD2, concentrations of active and total TGF-β were also decreased in SLE. After learning that IL-2 and TNF-α enhance lymphocyte production of active TGF-β, we found that the addition of these cytokines was unable to increase active TGF-β to normal concentrations. Although we observed that IL-10 inhibited the production of active TGF-β, antagonism of this cytokine was unable to completely correct the defect. In two SLE patients with B cell hyperactivity, spontaneous IgG production was almost abolished by the combination of TGF-β and IL-2. Therefore, decreased production of each of these cytokines in SLE could be important in the perpetuation of B cell hyperactivity.