Deficiency of miR-15a/16 upregulates NKG2D in CD8+ T cells to exacerbate dextran sulfate sodium-induced colitis.

Xiaoqin Jia, Yingying Wei, Xin Miao, Tao Zhu, Xiangyu Hu, Zhijie Lin, Weiming Xiao, Yu Zhang, Zhengbing Wang, Weijuan Gong

Biochemical and biophysical research communications 2021 May 21

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The miR-15a/16 gene cluster is located in human chromosome 13 (13q14.3) and mouse chromosome 14 (14qC3). These genes are involved in cancer development and immune regulation. Our group has previously verified the binding of the 3'-untranslated region of NKG2D gene by miR-16 through dual-luciferase reporter assay. Herein, we found that miR-16 overexpression inhibited the NKG2D expression of CD8+ T cells, and that CD8+ NKG2D+ T cell frequency increased in miR-15/16-/- mice. CD8+ NKG2D+ T cells derived of miR-15/16-/- mice displayed activatory phenotype with enhanced IFN-γ production and cytotoxicity. The transfection of lentivirus containing antago-miR-16 sequences enhanced the NKG2D expression level of CD8+ T cells. However, no significant differences in CD8+ NKG2D+ T cell frequencies existed between wild-type and miR-15/16-transgenic mice because NKG2D was not expressed on the rest CD8+ T cells. When CD8+ T cells of miR-15/16-transgenic mice were treated with IL-2 in vitro, the magnitude of NKG2D expression and activation of CD8+ T cells was lower than that of wild-type mice. miR-15/16-/- mice showed that the exacerbation of colitis induced by dextran sulfate sodium (DSS) with more CD8+ T cells accumulated in inflamed colons, whereas miR-15/16-transgenic mice ameliorated DSS-induced colitis with less infiltration of CD8+ T cells. When NKG2D+ cells were depleted with NKG2D antibody in miR-15/16-/- mice, the aggravated colitis disappeared. All these results demonstrated that NKG2D could be upregulated by decreased miR-16 in CD8+ T cells to mediate inflammation. Thus, gene therapy based on the overexpression of miR-16 in CD8+ T cells can be used for patients with inflammatory diseases. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Xiaoqin Jia, Yingying Wei, Xin Miao, Tao Zhu, Xiangyu Hu, Zhijie Lin, Weiming Xiao, Yu Zhang, Zhengbing Wang, Weijuan Gong. Deficiency of miR-15a/16 upregulates NKG2D in CD8+ T cells to exacerbate dextran sulfate sodium-induced colitis. Biochemical and biophysical research communications. 2021 May 21;554:114-122