miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion
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Qing Li1,2,*, Nathan Johnston3,*, Xiufen Zheng3,4, Hongmei Wang1, Xusheng Zhang3, Dian Gao1, Weiping Min1,4
1Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China
2Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
3Department of Surgery, Pathology and Oncology, Western University, London, Canada
4Lawson Health Research Institute, London, Canada
*These authors have contributed equally to this work
Weiping Min, email: firstname.lastname@example.org
Xiufen Zheng, email: email@example.com
Keywords: exhausted T cells, miR-28, inhibitor receptors, PD1, melanoma
Received: April 21, 2016 Accepted: June 13, 2016 Published: July 20, 2016
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.
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