Tetanus toxoid (tet) immunization of normal humans leads to the transient appearance in the circulation of large lymphoblastoid (LB) B cells, which spontaneously secrete IgG-tet in short-term cultures. The present work examines the effect of endogenous natural killer (NK) cells, as defined as CD 16+ cells, on the LB B cell subset. NK cell depletion by monoclonal antibody (Leu11) and complement (C)-mediated lysis from LB B cell containing populations eliminated 76 +/- 7% of the cytotoxic activity against 51Cr-K-562 cells, and, in contrast, enhanced 2.7 +/- 0.3 times IgG-tet secretion. Cells untreated, treated with Leu11 alone, C alone, or with an irrelevant monoclonal antibody and C were used as controls. Furthermore, the increased IgG-tet production after NK depletion could be reversed by adding autologous CD 16(+)-enriched populations. Limiting dilution analysis revealed that the NK removal enhancement of IgG-tet production was due to an augmentation (3.18 +/- 0.63 times) of the precursor frequency of spontaneous antibody-secreting cells in NK-depleted cells with respect to control populations. Finally, the spontaneous IgG-tet-producing cells present in NK-depleted and control populations were the same since they produced similar quantities of antibody on a per cell basis and exhibited identical large size, as determined by 1 x G sedimentation technique. NK cells, therefore, exert a strong inhibitory effect on LB B cells by preventing the development of a considerable part of their precursors. This mechanism might be of importance in the control of LB B cells in vivo.