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Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells

Nature Immunology volume 7, pages 929–936 (2006)Cite this article

Abstract

Interleukin 27 (IL-27) was first characterized as a proinflammatory cytokine with T helper type 1–inducing activity. However, subsequent work has demonstrated that mice deficient in IL-27 receptor (IL-27Rα) show exacerbated inflammatory responses to a variety of challenges, suggesting that IL-27 has important immunoregulatory functions in vivo. Here we demonstrate that IL-27Rα-deficient mice were hypersusceptible to experimental autoimmune encephalomyelitis and generated more IL-17-producing T helper cells. IL-27 acted directly on effector T cells to suppress the development of IL-17-producing T helper cells mediated by IL-6 and transforming growth factor-β. This suppressive activity was dependent on the transcription factor STAT1 and was independent of interferon-γ. Finally, IL-27 suppressed IL-6-mediated T cell proliferation. These data provide a mechanistic explanation for the IL-27-mediated immune suppression noted in several in vivo models of inflammation.

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Figure 1: Il27ra−/− mice develop severe EAE.
Figure 2: Cytokine production in response to MOG(35-55).
Figure 3: Increased IL-17 production in the CNS of Il27ra−/− mice during EAE.
Figure 4: TH-17 cell differentiation is suppressed by IL-27.
Figure 5: IL-27 acts directly on CD4+ T cells to suppress IL-17 production.
Figure 6: Suppression of TH-17 cell differentiation by IL-27 is dependent on activation of STAT1.
Figure 7: IL-27 antagonizes IL-6-induced proliferation.

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Acknowledgements

We thank W. Ouyang and B. Irving for critical reading of the manuscript; N. Pal and the Genentech Histology Laboratory for processing and staining of histological specimens; and R. Scott and S. Liu for animal husbandry.

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Author notes

  1. Marcel Batten and Ji Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, South San Francisco, 94080, California, USA

    Marcel Batten, Ji Li, Sothy Yi, Noelyn M Kljavin, James Lee, Frederic J de Sauvage & Nico Ghilardi

  2. Department of Pathology, Genentech, South San Francisco, 94080, California, USA

    Dimitry M Danilenko

  3. Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Belgium

    Sophie Lucas

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Correspondence to Nico Ghilardi.

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Supplementary information

Supplementary Fig. 1

EAE in Il27ra−/− mice is ameliorated by treatment with a neutralizing anti-IL-17A antibody. (PDF 42 kb)

Supplementary Fig. 2

Quantitative PCR analysis of IL23r expression. (PDF 55 kb)

Supplementary Fig. 3

Additive effect of IFN-γ and IL-27 in protection against EAE. (PDF 49 kb)

Supplementary Fig. 4

IL-27 induced IL-17 in STAT-1-deficient cells is independent of APC. (PDF 65 kb)

Supplementary Fig. 5

Natural regulatory T cell number is unchanged IL-27r−/− mice. (PDF 131 kb)

Supplementary Table 1

Primer sequences. (PDF 7 kb)

Supplementary Methods (PDF 14 kb)

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Batten, M., Li, J., Yi, S. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells. Nat Immunol 7, 929–936 (2006). https://doi.org/10.1038/ni1375

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