IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis

To study a potential IL-12p40-dependent but IL-12p75-independent agonistic activity regulating the immune response against Salmonella Enteritidis, the course of infection in IL-12p35-deficient mice (IL-12p35(-/-), capable of producing IL-12p40) was compared with that of IL-12p40(-/-) mice. Mice lack ing IL-12p40 revealed a higher mortality rate and higher bacterial organ bu rden than mice capable of producing IL-12p40. This phenotype was found in b oth genetically susceptible (BALB/c, Ity(s)) and resistant mice (129Sv/Ev, Ity(r)) indicating Ity-independent mechanisms. The more effective control o f bacteria in the IL-12p35(-/-) mice was associated with elevated serum IFN -gamma and TNF-alpha levels. In contrast, IL-12p40(-/-) mice showed reduced IFN-gamma production, which was associated with significantly elevated ser um IgE levels. Early during infection (days 3 and 4 postinfection), as well as late (day 20 postinfection), the number of infected phagocytes was stro ngly increased in the absence of IL-12p40 indicating impaired bactericidal activity when IL-12p40 was missing. Liver histopathology revealed a decreas ed number of mononuclear granulomas in IL-12p40(-/-) mice. Depletion of CD4 (+) or CD8(+) T lymphocytes in vivo suggested that both T cell subpopulatio ns contribute to the IL-12p40-dependent protective functions. Analysis of I L-12p40 vs IL-23p19 mRNA expression revealed an up-regulation of only, IL-1 2p40 mRNA during Salmonella infection. Together these data indicate that IL -12p40 can induce protective mechanisms during both the innate and the adap tive type 1 immune response in Salmonella infection. This novel activity of IL-12p40 complements the well described dominant and essential role of IL- 12p75 in protective immunity to Salmonella infection.