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

Area of Science:

• Immunology
• Molecular Biology
• Cellular Signaling

Background:

• T-cell immunoglobulin and mucin domain-3 (Tim-3) is a key regulator of T-cell dysfunction in chronic infections and cancer.
• The signaling pathways driving Tim-3 expression remain largely unknown.

Purpose of the Study:

• To elucidate the signaling pathways that regulate Tim-3 expression.
• To investigate the role of the IL-27/NFIL3 axis in T-cell function and dysfunction.

Main Methods:

• Investigated the effect of IL-27 on Tim-3 expression in T cells.
• Utilized chromatin remodeling assays and in vivo models.
• Analyzed T-cell function in IL-27 receptor knockout mice.

Main Results:

• IL-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes Tim-3 expression and IL-10 production.
• The IL-27/NFIL3 signaling axis is essential for Tim-3 induction in vivo.
• IL-27-conditioned T helper 1 cells show reduced effector function and NFIL3-dependent inhibition.
• Tumor-infiltrating lymphocytes lacking IL-27R show reduced NFIL3 and Tim-3 expression, leading to impaired T-cell dysfunction and enhanced tumor growth control.

Conclusions:

• Identified a novel IL-27/NFIL3 signaling axis that regulates effector T-cell responses.
• This axis induces Tim-3, IL-10, and T-cell dysfunction, impacting chronic infections and cancer.
• The findings provide insights into mechanisms of T-cell exhaustion and potential therapeutic targets.