Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection

Effector responses induced by polarized CD4+ T helper 2 (Th2) cells drive nonhealing responses in BALB/c mice infected with Leishmania major. Th2 cytokines IL-4 and IL-13 are known susceptibility factors for L. major infection in BALB/c mice and induce their biological functions through a common receptor, the IL-4 receptor α chain (IL-4Rα). IL-4Rα-deficient BALB/c mice, however, remain susceptible to L. major infection, indicating that IL-4/IL-13 may induce protective responses. Therefore, the roles of polarized Th2 CD4+ T cells and IL-4/IL-13 responsiveness of non-CD4+ T cells in inducing nonhealer or healer responses have yet to be elucidated. CD4+ T cell-specific IL-4Rα (LckcreIL- 4Rα-/lox) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Rα signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4+ T cells. Efficient deletion was confirmed by loss of IL-4Rα expression on CD4+ T cells and impaired IL-4-induced CD4+ T cell proliferation and Th2 differentiation. CD8+, γδ +, and NK-T cells expressed residual IL-4Rα, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Rα-/lox BALB/c mice, which developed ulcerating lesions following infection with L. major, LckcreIL-4Rα-/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-4Rα -/lox mice correlated with reduced numbers of IL-10-secreting cells and early IL-12p35 mRNA induction, leading to increased delayed type hypersensitivity responses, interferon-γ production, and elevated ratios of inducible nitric oxide synthase mRNA/parasite, similar to C57BL/6 mice. These data demonstrate that abrogation of IL-4 signaling in CD4+ T cells is required to transform nonhealer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Rα signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4+ T cells induce protective responses. © 2007 Radwanska et al.