BCL-6-deficient mice reveal an IL-4-independent, STAT-6-dependent pathway that controls susceptibility to infection by Leishmania major

The BCL-6 gene negatively regulates Th2 responses as shown by the finding t hat BCL-6-deficient (BCL-6(-/-)) mice develop a lethal Th2-type inflammator y disease. The response of inbred mouse strains to infection with Leishmani a major is under genetic control; BALB/c mice are susceptible and develop a progressive parasite burden, whereas most other common laboratory strains of mice are resistant to infection. We found that BCL-6-/- mice on a resist ant genetic background (C57BL/6 x 129 intercrossed mice) were highly suscep tible to L, major infection; they resembled BALB/c mice in terms of lesion size, parasite load, and the production of Th2 cytokines, BCL-6(-/-)IL-4(-/ -) double-mutant mice mere also susceptible to L, major infection and produ ced 10-fold higher levels of the Th2 cytokine IL-13 than IL-4(-/-) litterma te controls. By contrast, BCL-6(-/-)STAT6(-/-) double mutant mice were resi stant to L, major infection despite also producing elevated levels of IL-13 . These results show that STAT6 is required for susceptibility to L. major infection and suggest that IL-13 signaling through STAT6 may contribute to a nonhealing, exacerbated L, major infection.