SummaryInfection of mice with the protozoan Leishmania major provides an excellent model to define the factors involved in T helper (Th) subset development, since Thl cells confer protection in resistant strains of mice, whereas Th2 cells are associated with the fatal outcome of susceptible mice. We previously found that interferon 3~ (IFN-v) was required for Thl cell development after infection of mice with L. major. In this report, we evaluate the contribution of natural killer (NK) cells to IFN-v levels early in L. major infection. NK cell activity was higher in resistant C3H/HeN mice than in susceptible BALB/c mice during the first week of infection, and removal of NK cells significantly decreased IFN-3' levels and promoted interleukin 4 (IL-4) production in both the draining lymph nodes and spleen. IFN-v production by NK cells required the presence of CD4 + T cells or IL-2, but not CD8 + T cells. Enhanced disease, as measured by parasite numbers and lesion development, was observed in NK cell-depleted mice. Furthermore, a comparison of the NK cell response and the subsequent parasite burden in several inbred strains of mice demonstrated that NK cells mediate early resistance to L. major. Together, these data indicate that the stimulation of NK cells, through the production of IFN-'),, plays an important role in initiating Thl cell differentiation in leishmaniasis and in controlling early resistance to L. major.A major advance in immunology was the demonstration that CD4 + Th cells are composed of subsets based upon the cytokines produced after stimulation, and that these distinct T cell subsets often influence the outcome of infection (1-4). CD4 + Thl cells produce IL-2 and IFN-% primarily mediate cell-mediated immunity, and are often associated with bacterial, protozoan, and viral infections (1, 2). In contrast, Th2 cells produce IL-4, IL-5, and IL-IO, mediate humoral and allergic responses, and are often associated with helminth infections (1, 2). Observations from several in vitro and in vivo models indicate that the cytokines present during primary antigen stimulation are a major factor in determining the differentiation pathway of naive T cells (5-10). The role of cytokines has been most clearly shown in vivo in the murine model of cutaneous leishmaniasis, where a single administration of anti-IFN-qr mAb before L. major infection promotes susceptibility (11,12) and inhibits the development of Thl cells (10). Moreover, injection of IFN-v with the parasites switches the early cytokine pattern in susceptible BALB/c mice from a Th2 to a Thl profile (10). Importantly, the changes in the cytokine pattern after treatment with either anti-IFN-3, or IFN-3' are apparent within 3 d of infection, suggesting that the cytokine environment at the time of antigen presentation is critical in Th cell subset development. The compelling evidence that IFN-3~ levels modulate Thl development in this model has led us to investigate the source of IFN-v during the first few days of infection.Two sources of IFN-7 have been descr...

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 (TH) cells. Vaccination of BALB/c mice with leishmanial antigens and interleukin-12 (IL-12) promoted the development of leishmanial-specific CD4+ TH1 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.

Leishmania are intracellular parasites of macrophages that cause a diverse range of diseases, from nonapparent infections to fatal visceral disease. Whether infected individuals heal depends on attributes of both the host and the species or strain of Leishmania. Murine models of cutaneous leishmaniasis have been studied extensively over the last decade in order to identify some of these host and parasite factors.' One of the principal findings is that the nature of the CD4' Th cell subset that develops determines if mice are able to heal or control their infections.* CD4' Thl cells, which mediate cell-mediated immunity, are the primary cell type associated with protection.

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