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The composition and signaling of the IL-35 receptor are unconventional

Nature Immunology volume 13, pages 290–299 (2012)Cite this article

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Abstract

Interleukin 35 (IL-35) belongs to the IL-12 family of heterodimeric cytokines but has a distinct functional profile. IL-35 suppresses T cell proliferation and converts naive T cells into IL-35-producing induced regulatory T cells (iTr35 cells). Here we found that IL-35 signaled through a unique heterodimer of receptor chains IL-12Rβ2 and gp130 or homodimers of each chain. Conventional T cells were sensitive to IL-35-mediated suppression in the absence of one receptor chain but not both receptor chains, whereas signaling through both chains was required for IL-35 expression and conversion into iTr35 cells. Signaling through the IL-35 receptor required the transcription factors STAT1 and STAT4, which formed a unique heterodimer that bound to distinct sites in the promoters of the genes encoding the IL-12 subunits p35 and Ebi3. This unconventional mode of signaling, distinct from that of other members of the IL-12 family, may broaden the spectrum and specificity of IL-35-mediated suppression.

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Figure 1: IL-12Rβ2 or gp130 is sufficient for IL-35-mediated suppression.
Figure 2: Both IL-12Rβ2 and gp130 are required for the expression of Ebi3 and Il12a, and conversion into iTr35 cells.
Figure 3: IL-35R-deficient Tconv cells are resistant to IL-35-mediated suppression in vivo.
Figure 4: IL-12Rβ2 and gp130 associate in the presence of IL-35 to form three receptors.
Figure 5: Expression of the IL-35R chains can be induced IL-2 and IL-27.
Figure 6: IL-35 signals via STAT1 and STAT4.
Figure 7: IL-35 uses a STAT1-STAT4 heterodimer to mediate interaction with the Ebi3 and Il12a promoters.
Figure 8: Structural models of the IL-12 family of cytokine receptor complexes.

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Acknowledgements

We thank D. Fairweather and J.A. Frisancho (Johns Hopkins University) for spleens and lymph nodes from Il12rb1−/− mice; M. Karin and S. Grivennikov (University of California at San Diego) for Il6stΔT mice; C. Hunter and J. Stumhofer (University of Pennsylvania) for Il27ra−/− mice; A. Satoskar and P. Reville (Ohio State University) for Stat1−/− mice; C. Drake and H.R. Yen (Johns Hopkins University) for Stat3ΔT mice; R. McEver (University of Oklahoma Health Sciences Center) for mice used to establish the colony of CD4cre × Il6stfl/fl mice at St. Jude Children's Research Hospital; M.J. Turk (Dartmouth College) for B16-F10 melanoma; J.A. Frisancho, S. Grivennikov, M. Karin, J. Stumhofer, P. Reville and H.R. Yen for assistance with the collection and shipping of spleens and lymph nodes; J. Partridge and P. Brindle for assistance in designing ChIP experiments; K. Forbes, A. Castellaw and A. Krause for the maintenance, breeding and genotyping of mouse colonies; R. Cross, G. Lennon and S. Morgan for flow cytometry; the staff of the Shared Animal Resource Center at St. Jude Children's Research Hospital for the animal husbandry; and the Hartwell Center for Biotechnology and Bioinformatics at St. Jude Children's Research Hospital for the synthesis of real-time PCR primers and probes. Supported by the US National Institutes of Health (R01 AI091977 to D.A.A.V. and F32 AI072816 to L.W.C.), NovoNordisk (D.A.A.V.), the National Cancer Institute Comprehensive Cancer Center (CA21765 to D.A.A.V.) and the American Lebanese Syrian Associated Charities (D.A.A.V.).

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Author notes

  1. Lauren W Collison and Greg M Delgoffe: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Lauren W Collison, Greg M Delgoffe, Clifford S Guy, Kate M Vignali, Vandana Chaturvedi, Peter J Murray & Dario A A Vignali

  2. Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA

    DeLisa Fairweather

  3. Department of Microbiology, The Ohio State University, Columbus, Ohio, USA

    Abhay R Satoskar

  4. Department of Molecular and Cellular Physiology and Department of Structural Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA

    K Christopher Garcia

  5. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Christopher A Hunter

  6. Department of Oncology and Department of Immunology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA

    Charles G Drake

  7. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Peter J Murray

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Contributions

L.W.C. designed (with help from D.A.A.V.) and executed a substantial proportion of the experiments, analyzed data and wrote the manuscript; G.M.D. did STAT coimmunoprecipitation and ChIP–ChIP-reChIP experiments, cytokine-receptor coimmunoprecipitation experiments, some phosphorylated STAT analysis and functional assays and wrote the manuscript; C.S.G. did confocal microscopy–FRET experiments; K.M.V. generated all constructs; V.C. did TH1 and TH2 polarization for receptor analysis; D.F., A.R.S., C.A.H. and C.G.D. provided mice; K.C.G. did structural modeling of cytokine receptor complexes; P.J.M. analyzed phosphorylated STAT by immunoblot; C.A.H., P.M., K.C.G., C.G.D. and K.M.V. commented on the manuscript; and D.A.A.V. conceived of the research, directed the study and wrote the manuscript.

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Correspondence to Dario A A Vignali.

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Competing interests

D.A.A.V., L.W.C. and K.M.V. have submitted (pending) patents and are entitled to a share of the income generated from licensing of those patent rights for commercial development; D.A.A.V. received support from a sponsored research agreement with NovoNordisk.

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Collison, L., Delgoffe, G., Guy, C. et al. The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol 13, 290–299 (2012). https://doi.org/10.1038/ni.2227

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