In this report we have analyzed the effect of recombinant interleukin 2 (rIL 2) and rIL 2-activated natural killer (NK) cells on the production of immunoglobulin isotypes by lipopolysaccharide (LPS)-stimulated spleen cells from nude mice. We found that rIL 2 induced a dose-dependent increase of IgG2a secretion and a concomitant inhibition of the secretion of other Ig isotypes. The analysis of the phenotype of LPS- and LPS+ rIL 2-stimulated nude spleen cells showed the appearance of a Thy-1+ asialo GM-1+slgM-CD3-CD4-CD8- cell population in the presence of rIL 2. A population with a similar phenotype was generated upon stimulation of spleen cells from nude mice with rIL 2 alone. These cells lysed YAC-1 cells, did not contain the alpha or gamma transcripts encoding the corresponding T cell receptor chains and are therefore NK cells activated by rIL 2. In co-culture experiments, these cells selectively increased the secretion of IgG2a by LPS-stimulated splenocytes from nude mice. The IgG2a induction triggered by rIL 2-activated NK cells, as well as that triggered by rIL 2, were blocked by an anti-interferon gamma monoclonal antibody. Thus, rIL 2 activated-NK cells enhance the production of IgG2a by secreting interferon-gamma.