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

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. Anderson () and Vijay K. Kuchroo ()
Additional contact information
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7072

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