IL-12 IS REQUIRED FOR NATURAL-KILLER-CELL ACTIVATION AND SUBSEQUENT T-HELPER-1 CELL-DEVELOPMENT IN EXPERIMENTAL LEISHMANIASIS

Infection of mice with the protozoan Leishmania major is an establishe d in vivo model for the definition of factors that contribute to CD4() T helper cell subset development. In the current study, a central ro le for IL-12 in directing both the innate and adaptive immune response s to L. major is established. We show that in vivo neutralization of I L-12 eliminates the NK cell cytotoxic response and IFN-gamma productio n by lymph node cells from 2-day L. major-infected C3H mice. Moreover, anti-IL-12 treatment abrogated Th1 cell development and enhanced Th2 cell development. Consistent with these results, elevated IL-12 p40 pr oduction and an increase in the number of IL-12 p40-producing cells we re observed within 1 day of infection in C3H mice. Because BALB/c mice lack an early NK cell response or a Th1-type immune response after L. major infection, we investigated the possibility that they had a defe ct in the ability to produce IL-12. Surprisingly, L. major infection s timulated IL-12 p40 production in BALB/c mice early after infection. F urther studies suggest that BALB/c mice are unable to generate an earl y IFN-gamma response because of the simultaneous production of IL-12 a nd cytokines that inhibit IL-12 function, such as TGF-beta, IL-4, and IL-10. Together, these data show that IL-12 regulates the immune respo nse to L. major, but that even when IL-12 is induced, Th1 cell develop ment may be interrupted by simultaneous production of inhibitory cytok ines.