An IL-27/NFIL3 Signalling Axis Drives Tim-3 and IL-10 Expression and T-cell Dysfunction

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Jan 24

PMID 25614966

Citations 112

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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