Zhu, ChenSakuishi, KaoriXiao, ShengSun, ZhiyiZaghouani, SarahGu, GuangxiangWang, ChaoTan, Dewar J.Wu, ChuanRangachari, ManuPertel, ThomasJin, Hyun-TakAhmed, RafiAnderson, AnaKuchroo, Vijay2015-08-032015Zhu, C., K. Sakuishi, S. Xiao, Z. Sun, S. Zaghouani, G. Gu, C. Wang, et al. 2015. “An IL-27/NFIL3 signaling axis drives Tim-3 and IL-10 expression and T cell dysfunction.” Nature communications 6 (1): 6072. doi:10.1038/ncomms7072. http://dx.doi.org/10.1038/ncomms7072.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820870SUMMARY The inhibitory receptor 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 signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling 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 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R−/− mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction.en-USJournal Article2015-08-0310.1038/ncomms7072