title: miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion.
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.
authors.affiliation: Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.|Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Surgery, Pathology and Oncology, Western University, London, Canada.
authors.forename: Nathan
authors.initials: N
authors.lastname: Johnston
authors.affiliation: Department of Surgery, Pathology and Oncology, Western University, London, Canada.|Lawson Health Research Institute, London, Canada.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgery, Pathology and Oncology, Western University, London, Canada.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.
authors.forename: Dian
authors.initials: D
authors.lastname: Gao
authors.affiliation: Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.|Lawson Health Research Institute, London, Canada.
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; C000723159:MIRN28 microRNA, mouse; D035683:MicroRNAs; D061026:Programmed Cell Death 1 Receptor
keywords: PD1; exhausted T cells; inhibitor receptors; melanoma; miR-28