ITY INFLUENCES THE PRODUCTION OF IFN-GAMMA BY MURINE SPLENOCYTES STIMULATED INVITRO WITH SALMONELLA-TYPHIMURIUM

The Ity-Lsh-Bcg genetic locus in the mouse has been documented to conf er innate resistance to at least three intracellular pathogens: Salmon ella typhimurium, Leishmania donovani, and Mycobacterium. Expression o f the resistance gene(s) results in a slower net growth of these patho gens in the reticuloendothelial system early postinfection. Although i t is clear that the resident macrophages in resistant mice are functio nally superior with regard to antimicrobial activity, the exact mechan ism(s) underlying the control exerted by this gene is not understood. Using S. typhimurium infection as a model, we have examined the influe nce of this resistance gene(s) on the production of IFN-gamma, a cytok ine known to play an important role in host-defense against several in tracellular pathogens. We compared IFN-gamma production by splenocytes from resistant (Ity(r)) and sensitive (Ity(s)) inbred mouse strains a fter stimulation in vitro with S. typhimurium. Spleen cells from Ity(r ) mouse strains produced significantly higher levels of IFN-gamma when compared to spleen cells obtained from Ity(s) mouse strains. Enhanced IFN-gamma production was not a generalized response to bacteria. List eria monocytogenes induced comparable levels of IFN-gamma production f rom both Ity(r) (CBA/J) and Ity(s) (C57BL/6) mice. Splenocytes from It y congenic mouse strains displayed similar differences in the level of IFN-gamma produced after S. typhimurium stimulation, with spleen cell s from the Ity(r) strain producing significantly higher levels of IFN- gamma when compared to spleen cells from the Ity(s) strain. A requirem ent for adherent cells and/or adherent cell-derived factors has been d ocumented for IFN-gamma production by S. typhimurium-stimulated spleno cytes. Interestingly, supernatant from adherent cells obtained from It y(r) mouse strains was found to induce the production of significantly higher levels of IFN-gamma when compared to adherent cell supernatant from Ity(s) strains. Nylon wool nonadherent cells from Ity(s) mouse s trains produced high levels of IFN-gamma when exposed to supernatants obtained from adherent cells of Ity(r) mouse strains. In contrast, nyl on wool nonadherent cells from Ity(r) mouse strains produced reduced l evels of IFN-gamma when exposed to supernatant obtained from adherent cells of Ity(s) mouse strains. Thus, modulation of IFN-gamma productio n appears to be a function of the Ity(r) gene(s). This study documents for the first time that the Ity locus may play a role in controlling resistance to Salmonella infection by regulating IFN-gamma production by NK cells.