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

Magdalena Radwanska, Antony J. Cutler, J. Claire Hoving, Stefan Magez, Christoph Holscher, Andreas Bohms, Berenice Arendse, Richard Kirsch, Thomas Hunig, James Alexander, Paul Kaye, Frank Brombacher

Research output: Contribution to journalArticle

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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 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 (LckcreIL-4Rα/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 CD4+T cells. Efficient deletion was confirmed by loss of IL-4Ra 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-4Ra, 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, LckcreIL-4Rα/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-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-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 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.
LanguageEnglish
Article numbere68
Pages0619-0629
Number of pages10
JournalPLOS Pathogens
Volume3
Issue number5
DOIs
Publication statusPublished - 11 May 2007

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Interleukin-4 Receptors
Leishmania major
Interleukin-4
Interleukin-13
T-Lymphocytes
Infection
Th2 Cells
Inbred C57BL Mouse
Interleukin-12 Subunit p35
Messenger RNA
Cutaneous Leishmaniasis
Delayed Hypersensitivity
Nitric Oxide Synthase Type II
Natural Killer Cells
Interleukin-10
Interferons
Parasites
Cell Proliferation
Cytokines
Phenotype

Keywords

  • cells
  • infection control

Cite this

Radwanska, M., Cutler, A. J., Hoving, J. C., Magez, S., Holscher, C., Bohms, A., ... Brombacher, F. (2007). Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. PLOS Pathogens, 3(5), 0619-0629. [e68]. https://doi.org/10.1371/journal.ppat.0030068
Radwanska, Magdalena ; Cutler, Antony J. ; Hoving, J. Claire ; Magez, Stefan ; Holscher, Christoph ; Bohms, Andreas ; Arendse, Berenice ; Kirsch, Richard ; Hunig, Thomas ; Alexander, James ; Kaye, Paul ; Brombacher, Frank. / Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. In: PLOS Pathogens. 2007 ; Vol. 3, No. 5. pp. 0619-0629.
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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 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 (LckcreIL-4Rα/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 CD4+T cells. Efficient deletion was confirmed by loss of IL-4Ra 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-4Ra, 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, LckcreIL-4Rα/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-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-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 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.",
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author = "Magdalena Radwanska and Cutler, {Antony J.} and Hoving, {J. Claire} and Stefan Magez and Christoph Holscher and Andreas Bohms and Berenice Arendse and Richard Kirsch and Thomas Hunig and James Alexander and Paul Kaye and Frank Brombacher",
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Radwanska, M, Cutler, AJ, Hoving, JC, Magez, S, Holscher, C, Bohms, A, Arendse, B, Kirsch, R, Hunig, T, Alexander, J, Kaye, P & Brombacher, F 2007, 'Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection' PLOS Pathogens, vol. 3, no. 5, e68, pp. 0619-0629. https://doi.org/10.1371/journal.ppat.0030068

Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. / Radwanska, Magdalena; Cutler, Antony J.; Hoving, J. Claire; Magez, Stefan; Holscher, Christoph; Bohms, Andreas; Arendse, Berenice; Kirsch, Richard; Hunig, Thomas; Alexander, James; Kaye, Paul; Brombacher, Frank.

In: PLOS Pathogens, Vol. 3, No. 5, e68, 11.05.2007, p. 0619-0629.

Research output: Contribution to journalArticle

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T1 - Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection

AU - Radwanska, Magdalena

AU - Cutler, Antony J.

AU - Hoving, J. Claire

AU - Magez, Stefan

AU - Holscher, Christoph

AU - Bohms, Andreas

AU - Arendse, Berenice

AU - Kirsch, Richard

AU - Hunig, Thomas

AU - Alexander, James

AU - Kaye, Paul

AU - Brombacher, Frank

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N2 - 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 (LckcreIL-4Rα/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 CD4+T cells. Efficient deletion was confirmed by loss of IL-4Ra 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-4Ra, 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, LckcreIL-4Rα/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-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-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 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.

AB - 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 (LckcreIL-4Rα/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 CD4+T cells. Efficient deletion was confirmed by loss of IL-4Ra 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-4Ra, 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, LckcreIL-4Rα/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in LckcreIL-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-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 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.

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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 May 11;3(5):0619-0629. e68. https://doi.org/10.1371/journal.ppat.0030068