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An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction

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Listed:
  • Chen Zhu

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Kaori Sakuishi

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Sheng Xiao

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Zhiyi Sun

    (New England Biolabs Inc.)

  • Sarah Zaghouani

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Guangxiang Gu

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Chao Wang

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Dewar J. Tan

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Chuan Wu

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Manu Rangachari

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Thomas Pertel

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Hyun-Tak Jin

    (Emory Vaccine Center, Emory University School of Medicine)

  • Rafi Ahmed

    (Emory Vaccine Center, Emory University School of Medicine)

  • Ana C. Anderson

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

  • Vijay K. Kuchroo

    (Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

Abstract

The inhibitory receptor T-cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of the T-cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signalling pathways that drive Tim-3 expression. Here, we demonstrate that interleukin (IL)-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes permissive chromatin remodelling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signalling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned T helper 1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumour-infiltrating lymphocytes from IL-27R−/− mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumour growth control. Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.

Suggested Citation

  • Chen Zhu & Kaori Sakuishi & Sheng Xiao & Zhiyi Sun & Sarah Zaghouani & Guangxiang Gu & Chao Wang & Dewar J. Tan & Chuan Wu & Manu Rangachari & Thomas Pertel & Hyun-Tak Jin & Rafi Ahmed & Ana C. Anders, 2015. "An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7072
    DOI: 10.1038/ncomms7072
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