PRODUCTION OF GAMMA-INTERFERON BY NATURAL-KILLER-CELLS FROM TAXOPLASMA GONDII-INFECTED SCID MICE - REGULATION BY INTERLEUKIN-10, INTERLEUKIN-12, AND TUMOR-NECROSIS-FACTOR-ALPHA

Previous studies of mice have implicated natural killer (NK) cells as mediators of protective activity against Toxoplasma gondii through the ir production of gamma interferon (IFN-gamma). In the present study, w e have compared NK-cell activity in infected and uninfected SCID mice. Our data reveal that infection results in increased levels of IFN-gam ma in serum and elevated NK-cell activity but that these NK cells were not cytotoxic for T. gondii-infected p815 cells. Treatment with anti- IFN-gamma antibody abrogated the increase in NK-cell activity and resu lted in earlier mortality of infected mice. In vivo treatment with ant i-asialo GM1 antiserum reduced NK cell activity and levels of IFN-gamm a in serum but did not alter time to death. Spleen cells from infected mice produced higher levels of IFN-gamma than those from uninfected m ice when stimulated in vitro with live T. gondii or parasite antigen p reparations. Further analysis revealed that interleukin 10 (IL-10) inh ibited, whereas tumor necrosis factor alpha (TNF-alpha) and 1L-12 enha nced, IFN-gamma production by spleen cells from infected or uninfected mice. The combination of IL-12 and TNF-alpha induced higher levels of IFN-gamma from whole spleen cells of infected mice than from those of uninfected mice. Depletion of the adherent cell population from the s pleen cells of infected mice led to a significant reduction in the lev els of IFN-gamma produced after stimulation with IL-12 plus TNF-alpha. Similar results did not occur with cells from uninfected mice. These data indicate that other cytokines produced by the adherent fell popul ation from infected mice may be involved in maximal production of IFN- gamma by NK cells stimulated with IL-12 and TNF-alpha. To assess the i mportance of endogenous IL-12, a polyclonal anti-IL-12 was administere d to infected SCID mice. This treatment led to earlier mortality, indi cating that endogenous IL-12 mediates resistance to T. gondii.