Our previous studies have indicated an important regulatory role for natural killer (NK) cells, a major constituent of the innate immune system in modulating antigen-specific responses. Herein, we have investigated the possible participation of these cells in regulating the polyclonal response as well. For these studies we have utilized heat-killed Brucella abortus (HKBA). Brucella abortus is a facultative intracellular bacterium that is pathogenic for both humans and animals. An outstanding feature of the infectious process is the rapid production of polyclonal antibodies, particularly of the IgG2c subclass, that bypasses the requirement for clonally specific antigen recognition. We report here that NK-cell depletion profoundly reduced the production of these polyclonal antibodies suggesting that activation of B cells by HKBA requires help from NK cells. This help may not be solely derived from NK-cell amplification of the cytokine circuit initiated by HKBA but may involve direct NK-B-cell interactions as suggested by results of in vitro analyses of NK induction of γ2a mRNA by B cells. These findings have therapeutic implications in that the induction of polyclonal Ig production may be more important for altering the chronic phase rather than the acute stage of infection by B. abortus.