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 chain (IL-4R). IL-4Rdeficient 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 cellspecific IL-4R (LckcreIL-4R/lox) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4R signaling during cutaneous leishmaniasis in the absence of IL-4responsive CD4 T cells. Efficient deletion was confirmed by loss of IL-4R expression on CD4 T cells and impaired IL-4induced CD4 T cell proliferation and Th2 differentiation. CD8, , and NKT cells expressed residual IL-4R, and representative nonT cell populations maintained IL-4/IL-13 responsiveness.
In contrast to IL-4R/lox BALB/c mice, which developed ulcerating lesions following infection with L. major, LckcreIL-4R/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-4R/lox mice correlated with reduced numbers of IL-10secreting cells and early IL-12p35 mRNA induction, leading to increased delayed type hypersensitivity responses, interferon- 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-4R signaling in L. major infection is revealed in which IL-4/IL-13responsive non-CD4 T cells induce protective responses.