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

TitleDeletion of IL-4Ralpha on CD4 T cells renders BALB/c mice resistant to Leishmania major infection.
Publication TypeJournal Article
Year of Publication2007
AuthorsRadwanska, M., A. J. Cutler, C. J Hoving, S. Magez, C. Holscher, A. Bohms, B. Arendse, R. Kirsch, T. Hunig, J. Alexander, P. Kaye, and F. Brombacher
JournalPLoS Pathog
Date Published2007 May 11
KeywordsAnimals, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Proliferation, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Interferon-gamma, Interleukin-10, Interleukin-12, Interleukin-4, Interleukin-4 Receptor alpha Subunit, Leishmania major, Leishmaniasis, Cutaneous, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide, Nitric Oxide Synthase Type II, Reverse Transcriptase Polymerase Chain Reaction, Th1 Cells, Th2 Cells

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 alpha chain (IL-4Ralpha). IL-4Ralpha-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 non-healer or healer responses have yet to be elucidated. CD4+ T cell-specific IL-4Ralpha (Lck(cre)IL-4Ralpha(-/lox)) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Ralpha signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4+ T cells. Efficient deletion was confirmed by loss of IL-4Ralpha expression on CD4+ T cells and impaired IL-4-induced CD4+ T cell proliferation and Th2 differentiation. CD8+, gammadelta+, and NK-T cells expressed residual IL-4Ralpha, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Ralpha(-/lox) BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck(cre)IL-4Ralpha(-/lox) mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(cre)IL-4Ralpha(-/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-gamma 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 non-healer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Ralpha signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4+ T cells induce protective responses.

Alternate JournalPLoS Pathog.
PubMed ID17500591
PubMed Central IDPMC1867380