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

(2007) PLOS PATHOGENS. 3(5). p.619-629
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Abstract
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 a chain (IL-4R alpha). IL-4R alpha 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-4R alpha (Lck(cre)IL-4R alpha(-/lox)) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4R alpha signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4(+) T cells. Efficient deletion was confirmed by loss of IL4R alpha expression on CD4(+) T cells and impaired IL-4-induced CD4(+) T cell proliferation and Th2 differentiation. CD8(+), gamma delta(+), and NK-T cells expressed residual IL-4R alpha, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4R alpha(-/lox) BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck(cre)IL-4R alpha(-/lox) mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(cre)IL-4R alpha(-/lox) mice correlated with reduced numbers of IL-10-secreting cells and early IL12-p35 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 nonhealer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4R alpha signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4(+) T cells induce protective responses.
Keywords
ALTERNATIVE MACROPHAGE ACTIVATION, PROGRESSIVE MURINE LEISHMANIASIS, DELAYED-TYPE HYPERSENSITIVITY, CUTANEOUS LEISHMANIASIS, INTERFERON-GAMMA, IL-4 RECEPTOR, SUSCEPTIBILITY FACTOR, TH2 RESPONSES, CUTTING EDGE, INTERLEUKIN-4

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Chicago
Radwanska, Magdalena, Antony J Cutler, J Claire Hoving, Stefan Magez, Christoph Holscher, Andreas Bohms, Berenice Arendse, et al. 2007. “Deletion of IL-4Rα on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania Major Infection.” Plos Pathogens 3 (5): 619–629.
APA
Radwanska, M., Cutler, A. J., Hoving, J. C., Magez, S., Holscher, C., Bohms, A., Arendse, B., et al. (2007). Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. PLOS PATHOGENS, 3(5), 619–629.
Vancouver
1.
Radwanska M, Cutler AJ, Hoving JC, Magez S, Holscher C, Bohms A, et al. Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. PLOS PATHOGENS. 2007;3(5):619–29.
MLA
Radwanska, Magdalena et al. “Deletion of IL-4Rα on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania Major Infection.” PLOS PATHOGENS 3.5 (2007): 619–629. Print.
@article{8528990,
  abstract     = {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 a chain (IL-4R alpha). IL-4R alpha 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-4R alpha (Lck(cre)IL-4R alpha(-/lox)) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4R alpha signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4(+) T cells. Efficient deletion was confirmed by loss of IL4R alpha expression on CD4(+) T cells and impaired IL-4-induced CD4(+) T cell proliferation and Th2 differentiation. CD8(+), gamma delta(+), and NK-T cells expressed residual IL-4R alpha, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4R alpha(-/lox) BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck(cre)IL-4R alpha(-/lox) mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(cre)IL-4R alpha(-/lox) mice correlated with reduced numbers of IL-10-secreting cells and early IL12-p35 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 nonhealer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4R alpha signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4(+) T cells induce protective responses.},
  author       = {Radwanska, Magdalena and Cutler, Antony J and Hoving, J Claire and Magez, Stefan and Holscher, Christoph and Bohms, Andreas and Arendse, Berenice and Kirsch, Richard and Hunig, Thomas and Alexander, James and Kaye, Paul and Brombacher, Frank},
  issn         = {1553-7366},
  journal      = {PLOS PATHOGENS},
  language     = {eng},
  number       = {5},
  pages        = {619--629},
  title        = {Deletion of IL-4R\ensuremath{\alpha} on CD4 T cells renders BALB/c mice resistant to Leishmania major infection},
  url          = {http://dx.doi.org/10.1371/journal.ppat.0030068},
  volume       = {3},
  year         = {2007},
}

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