STAT-4 mediated IL-12 signaling pathway is critical for the development ofprotective immunity in cutaneous leishmaniasis

Recent studies have demonstrated that two IL-12 signaling pathways, a STAT4 -dependent and STAT4-independent, are involved in the development of a Th1- like response. To determine their roles in the development of protective im munity against Leishmania major, we monitored progression of cutaneous Leis hmania major infection in STAT4-deficient mice (STAT4-/-) compared to simil arly infected wild-type (STAT4+/+) mice. Although the onset of lesion growt h was delayed in STAT4-/- mice during the early phase of infection, these m ice eventually developed large, non-healing lesions, whereas STAT4+/+ mice resolved their lesions. As infection progressed, both STAT4+/- and STAT4-/- mice infected with L. major displayed similar titers of Leishmania-specifi c IgG1 and IgE but later produced lower IgG2a. On days 20 and 40 post-infec tion, Leishmania antigen-stimulated lymph node cells from STAT4-/- mice pro duced significantly lower amounts of IFN-gamma than those from STAT4+/+ mic e as measured by enzyme-linked immunosorbent assay. There was no significan t difference, however, in IL-4 and IL-12 production between the two groups. These results indicate that STAT4-mediated IL-12 signaling is critical for the development of protective Th1 response following L. major infection in genetically resistant mice. Additionally, they demonstrate that, although genetically resistant mice lacking STAT4 signaling pathway develop large, n on-healing lesions, they do not default towards a Th2-like response.