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Programmed death ligand-1 (PD-L1) is a critical regulator of T cell function contributing to peripheral immune tolerance. Although it has been shown that posttranscriptional regulatory mechanisms control PD-L1 expression in cancer, it remains unknown whether such regulatory loops operate also in non-transformed cells. Here we studied PD-L1 expression in human dermal lymphatic endothelial cells (HDLECs), which play key roles in immunity and cancer. Treatment of HDLECs with the pro-inflammatory cytokines IFN-γ and TNF-α synergistically up-regulated PD-L1 expression. IFN-γ and TNF-α also affected expression of several microRNAs (miRNAs) that have the potential to suppress PD-L1 expression. The most highly up-regulated miRNA following IFN-γ and TNF-α treatment in HDLECs was miR-155, which has a central role in the immune system and cancer. Induction of miR-155 was driven by TNF-α, the effect of which was significantly enhanced by IFN-γ. The PD-L1 3'-UTR contains two functional miR-155-binding sites. Endogenous miR-155 controlled the kinetics and maximal levels of PD-L1 induction upon IFN-γ and TNF-α treatments. We obtained similar findings in dermal fibroblasts, demonstrating that the IFN-γ/TNF-α/miR-155/PD-L1 pathway is not restricted to HDLECs. These results reveal miR-155 as a critical component of an inflammation-induced regulatory loop controlling PD-L1 expression in primary cells.

Original publication

DOI

10.1074/jbc.m117.809053

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

24/10/2017

Volume

292

Pages

20683 - 20693

Addresses

From the Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD and.

Keywords

Endothelium, Lymphatic, Cells, Cultured, Dermis, Humans, Tumor Necrosis Factor-alpha, Recombinant Proteins, MicroRNAs, RNA, Small Interfering, 3' Untranslated Regions, Microscopy, Fluorescence, Gene Expression Profiling, Gene Expression Regulation, RNA Interference, Binding Sites, Base Sequence, Response Elements, Kinetics, Genes, Reporter, Interferon-gamma, B7-H1 Antigen