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

• Type of Material: Article
• Authors: Chen Zhu, Harvard University; Kaori Sakuishi, Harvard University; Sheng Xiao, Harvard University; Zhiyi Sun, New England Biolabs Inc.; Sarah Zaghouani, Harvard University; Guangxiang Gu, Harvard University; Chao Wang, Harvard University; Dewar J. Tan, Harvard University; Chuan Wu, Harvard University; Manu Rangachari, Harvard University; Thomas Pertel, Harvard University; Hyun-Tak Jin, Emory University; Rafi Ahmed, Emory University; Ana C. Anderson, Harvard University; Vijay K. Kuchroo, Harvard University
• Language: English
• Date: 2015-01-23
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms7072
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 6
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (VKK: P01 AI073748, R01NS045937, NS030843, P01NS038037, P01AI056299; SX: K01DK090105), Ragon Institute of MGH, MIT and Harvard Innovation Award (VKK and CZ), and the American Cancer Society (ACA: RSG-11-057-01-LIB).; EMD Serono Canada/endMS Network Transitional Career Development Award from the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation (MR).
• Keywords: Science & Technology; CD4(+); INTERLEUKIN-27; EXHAUSTION; T cells; PD-1 EXPRESSION; CHRONIC VIRAL-INFECTION; CUTTING EDGE; Multidisciplinary Sciences; Gene expression; HELPER TYPE-1; PROINFLAMMATORY CYTOKINE PRODUCTION; Science & Technology - Other Topics; IL-27; Immunosuppression; AUTOIMMUNE; Cell signalling
• Research Categories: Biology, Genetics; Health Sciences, Immunology; Biology, Virology

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.