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miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion
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 sta...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288217/ https://www.ncbi.nlm.nih.gov/pubmed/27447564 http://dx.doi.org/10.18632/oncotarget.10731 |
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author | Li, Qing Johnston, Nathan Zheng, Xiufen Wang, Hongmei Zhang, Xusheng Gao, Dian Min, Weiping |
author_facet | Li, Qing Johnston, Nathan Zheng, Xiufen Wang, Hongmei Zhang, Xusheng Gao, Dian Min, Weiping |
author_sort | Li, Qing |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5288217 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-52882172017-02-07 miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion Li, Qing Johnston, Nathan Zheng, Xiufen Wang, Hongmei Zhang, Xusheng Gao, Dian Min, Weiping Oncotarget Research Paper 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. Impact Journals LLC 2016-07-20 /pmc/articles/PMC5288217/ /pubmed/27447564 http://dx.doi.org/10.18632/oncotarget.10731 Text en Copyright: © 2016 Li et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Li, Qing Johnston, Nathan Zheng, Xiufen Wang, Hongmei Zhang, Xusheng Gao, Dian Min, Weiping miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion |
title | miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion |
title_full | miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion |
title_fullStr | miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion |
title_full_unstemmed | miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion |
title_short | miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion |
title_sort | mir-28 modulates exhaustive differentiation of t cells through silencing programmed cell death-1 and regulating cytokine secretion |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288217/ https://www.ncbi.nlm.nih.gov/pubmed/27447564 http://dx.doi.org/10.18632/oncotarget.10731 |
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