Infections in mice with Leishmania major are used to study Th cell subset development and regulation, since some strains of mice, such as C3H, develop a Th1 cell response and heal, while other strains, such as BALB/c, develop a Th2 phenotype and exhibit chronic disease. It is widely believed that once the Th2 cell response is established in BALB/c mice, it is difficult to alter. However, a combination of IL-12 treatment and chemotherapy can induce healing in BALB/c mice with an established Th2 cell response. Moreover, we found that while C3H mice develop a Th2 phenotype when given anti-IL-12 mAb, they can switch to a Th1 cell response once mAb treatment is terminated. Therefore, the goal of this thesis was to characterize the factors controlling the switch from a Th2 to a Th1 cell phenotype in these two models. We examined the effects of a low and high parasite burden on the regulation of BALB/c T cell subsets by adoptively transferring cells with defined phenotypes into BALB/c scid mice. In these studies, we found that a high parasite burden does not directly inhibit type 1 cell development or effector function, but rather exerts its inhibitory function only in the presence of a type 2 cell population. Even though anti-IL-12-treated C3H mice contained high numbers of parasites during the first 4 weeks, similar to BALB/c mice, once the anti-IL-12-treatment was terminated these animals developed a Th1 cell response and healed. We show that the critical factors for developing Th1 cells in the presence of an ongoing Th2 cell response in anti-IL-12-treated C3H mice are the continued production of, and responsiveness to, IL-12. Thus, we found that, in contrast to a population of Th2 cells from BALB/c mice, a Th2 cell population from anti-IL-12-treated C3H mice contained a T cell population which responded to IL-12 by increasing the IL-12 receptor and IFN-γ production. Overall, our results are the first to demonstrate that the maintenance of a Th2 cell response during an infection, and the ability to alter that response, may differ depending upon the genetic background of the host
