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

Nat Commun. 2015 Jan 23;6:6072. doi: 10.1038/ncomms7072.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • Chromatin / metabolism
  • Clonal Anergy / immunology
  • Gastrointestinal Tract / pathology
  • Hepatitis A Virus Cellular Receptor 2
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-10 / metabolism*
  • Interleukin-27 / deficiency
  • Interleukin-27 / metabolism*
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Receptors, Virus / metabolism*
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • T-Box Domain Proteins / metabolism

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Chromatin
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukin-27
  • Nfil3 protein, mouse
  • Receptors, Virus
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interleukin-10