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Updated: Mar 17, 2026
Development and Functional Characterization of Murine Tolerogenic Dendritic Cells
Published on: May 18, 2018
miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating
Qing Li1,2, Nathan Johnston3, Xiufen Zheng3,4
1Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.
Abstract:
T cell exhaustion is a state of T cell dysfunction that arises during many cancer. miRNAs are one of major gene regulators which result in translational inhibition and/or mRNA degradation. We hypothesized that miRNAs exist that can silence PD1 and act as a modulator in vitro to revert exhaustive status of T cells. We demonstrated that the exhausted T cells with inhibitory receptors (IRs) are significantly increased in the melanoma-bearing mice. Meanwhile, the differentiated miRNA profiles in PD1+ exhaustive T cells were identified using a miRNA array; 11 miRNAs were observed with significant altered levels in the exhausted T cells isolated from melanoma-bearing mice. Among those identified miRNA candidates, miR-28 was capable of binding to multiple IRs based on an in silico analysis and subsequently silencing PD1, as demonstrated by a dual luciferase assay. Moreover, the expression of PD1 was attenuated after transfection with miR-28 mimic. The ability of miR-28 in regulating T cell exhaustion was further evidenced by the fact that the expression of PD1, TIM3 and BTLA of exhausted T cells was increased by the inhibitor of miR28. On the other hand, miR-28 also regulated the PD1+ Foxp3+ and TIM3+ Foxp3+ exhaustive Treg cells in vitro. miR-28 regulating T cell exhaustion was also observed by its ability in reinstalling impaired secretion of cytokines IL-2 and TNF-α by exhausted T cells. This study is the first to discover the effect of miR-28 on T cell exhaustion, providing novel targets with potential use as therapeutic markers in cancer immunotherapy.
Insights
MicroRNAs can regulate T cell exhaustion, a key factor in cancer. This study identifies miR-28 as a novel microRNA that silences PD1, potentially reversing T cell dysfunction in cancer immunotherapy.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- T cell exhaustion is a state of T cell dysfunction observed in various cancers, characterized by increased inhibitory receptors (IRs).
- MicroRNAs (miRNAs) are crucial gene regulators involved in translational inhibition and mRNA degradation, offering potential therapeutic targets.
Purpose of the Study:
- To investigate the role of miRNAs in regulating T cell exhaustion, specifically focusing on their ability to silence PD1.
- To identify specific miRNAs that modulate T cell exhaustion in the context of melanoma.
Main Methods:
- Profiling of miRNA expression in PD1+ exhausted T cells from melanoma-bearing mice.
- In silico analysis to predict miRNA binding sites on IRs.
- Dual luciferase assays to confirm miRNA-target interactions and gene silencing.
- In vitro experiments using miRNA mimics and inhibitors to assess the impact on T cell exhaustion markers and cytokine secretion.
Main Results:
- Eleven miRNAs showed significantly altered levels in exhausted T cells; miR-28 was identified as a key regulator.
- miR-28 directly binds to and silences PD1, as confirmed by luciferase assays and reduced PD1 expression upon miR-28 mimic transfection.
- Inhibition of miR-28 led to increased expression of PD1, TIM3, and BTLA in exhausted T cells.
- miR-28 demonstrated the ability to regulate exhausted regulatory T cells (Tregs) and restore impaired IL-2 and TNF-α secretion.
Conclusions:
- This study is the first to demonstrate that miR-28 plays a significant role in regulating T cell exhaustion.
- miR-28's ability to silence PD1 and modulate T cell function offers a novel therapeutic target for cancer immunotherapy.
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