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Deletion of IL-4Rά on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania major Infection

Radwanska, M. and Cutler, A.J. and Hoving, J.C. and Magez, S. and Holscher, C. and Bohms, A. and Arendse, B. and Kirsch, R. and Hunig, T. and Alexander, J. and Kaye, P. and Brombacher, F. (2007) Deletion of IL-4Rά on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania major Infection. PLOS Pathogens, 3 (5). 0619-0629. ISSN 1553-7366

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Abstract

Effector responses induced by polarized CD4þ 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 a chain (IL-4Ra). IL-4Ra-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 CD4þ T cells and IL-4/IL-13 responsiveness of non-CD4þ T cells in inducing nonhealer or healer responses have yet to be elucidated. CD4þ T cell-specific IL-4Ra (LckcreIL-4Rά/lox) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Ra signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4þ T cells. Efficient deletion was confirmed by loss of IL-4Ra expression on CD4þ T cells and impaired IL-4-induced CD4þ T cell proliferation and Th2 differentiation. CD8þ, cdþ, and NK-T cells expressed residual IL-4Ra, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Rά/lox BALB/c mice, which developed ulcerating lesions following infection with L. major, LckcreIL-4Rά/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-4Rά/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-c 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 CD4þ T cells is required to transform nonhealer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Ra signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4þ T cells induce protective responses.