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

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms7072

2041-1723

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, Vijay K. Kuchroo,

Bioactive Compounds and Antitumor Agents

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. Tim-3 is an inhibitory molecule that suppresses T-cell responses. Here the authors show that the cytokine IL-27, acting through the transcription factor NFIL3, induces Tim-3 in vivo, and that IL-27-conditioned Th1 cells have poor effector function.