Protection induced by vaccination depends on the capacity of the vaccine to elicit an appropriate immune response. In leishmaniasis, protection requires leishmanial-specific CD4 ⁺ T helper (T _H ) cells. Vaccination of BALB/c mice with leishmanial antigens and interleukin-12 (IL-12) promoted the development of leishmanial-specific CD4 ⁺ T _H 1 cells. These mice were resistant to subsequent infection with Leishmania major . Thus, IL-12 is an effective adjuvant for the initiation of protective cell-mediated immunity against leishmaniasis and may be an important component in other vaccines that need to induce cell-mediated immunity.

Infection of mice with the protozoan Leishmania major is an established in vivo model for the definition of factors that contribute to CD4+ T helper cell subset development. In the current study, a central role for IL-12 in directing both the innate and adaptive immune responses to L. major is established. We show that in vivo neutralization of IL-12 eliminates the NK cell cytotoxic response and IFN-gamma production 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 production and an increase in the number of IL-12 p40-producing cells were 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 defect in the ability to produce IL-12. Surprisingly, L. major infection stimulated IL-12 p40 production in BALB/c mice early after infection. Further studies suggest that BALB/c mice are unable to generate an early IFN-gamma response because of the simultaneous production of IL-12 and 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 response to L. major, but that even when IL-12 is induced, Th1 cell development may be interrupted by simultaneous production of inhibitory cytokines.