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 (Lck(cre)IL-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, Lck(cre)IL-4Rα(−/lox) mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(cre)IL-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.